B-lactam compounds

ABSTRACT

Penem derivs. and analogues of formula (I) and their salts. R1 = H or 1-hydroxyethyl in which the OH is opt. protected; R2, R3 = H or a protecting gp.; X = CHR4 or S; R4 = H or 103C alkyl; Y = NR5R6, N = C(NR7R7)2, opt. protected OH, 1-3C alkoxy, hydrazino opt. substd. by 1-3C alkyl or NHOR8; R5, R6 = H, 1-5C alkyl, 3-4C alkenyl, aryl-(1-3C)alkyl, 1-5C substd. alkyl or pyridyl; or R5+ R6 form alkylene opt. interrupted by O, S or N-(1-3C)alkyl to complete an opt. substd. 3- to 7-membered cyclic amino gp. opt. contg. a double bond(s) in the ring; R7 = H or 1-3C alkyl; R8 = H, protecting gp. or 1-3C alkyl.

This is a continuation of application Ser. No. 608,618, filed May 9,1984, now abandoned.

FIELD OF THE INVENTION

This invention relates to novel β-lactam compounds and a process forproducing the same. More particularly, this invention relates to novelβ-lactam compounds belonging to carbapenem or penem derivatives anduseful as antimicrobial agents or intermediates therefor and a processfor producing the same.

BACKGROUND OF THE INVENTION

Since the discovery of thienamycin having a potential antimicrobialactivity against Gram negative and Gram positive bacteria, studies onsyntheses of carbapenem or penem derivatives which are analoguous tothienamycin have been widely developed.

The present inventors have conducted intensive investigations onsyntheses of carbapenem or penem derivatives and, as a result, foundthat carbapenem or penem derivatives having, as their 2-side chain, asubstituent easily derived from 4-hydroxy-proline, i.e., a substitutedpyrrolidinyl group carrying a carbonyl group substituted with varioussubstituents on its 2-position, exhibit potential antimicrobial activityand are useful as medicines or are important intermediates for compoundspossessing antimicrobial activity, and thus completed the presentinvention.

SUMMARY OF THE INVENTION

The present invention relates to a novel β-lactam compound representedby the formula (I): ##STR1## wherein R₁ represents a hydrogen atom,1-hydroxyethyl group or a 1-hydroxyethyl group in which the hydroxygroup is protected with a protecting group; R₂ represents a hydrogenatom or a protecting group for an amino group; R₃ represents a hydrogenatom or a protecting group for a carboxyl group; X represents asubstituted or unsubstituted methylene group of the formula (1):##STR2## wherein R₄ represents a hydrogen atom or an alkyl group having1 to 3 carbon atoms, or a sulfur atom; and Y represents a group of theformula (2): ##STR3## wherein R₅ and R₆, which may be the same ordifferent, each represents a hydrogen atom, an alkyl group having 1 to 5carbon atoms, an alkenyl group having 3 to 4 carbon atoms, an aralkylgroup having 1 to 3 carbon atoms in its alkyl moiety, a substitutedalkyl group having 1 to 5 carbon atoms or a pyridyl group, or R₅ and R₆are taken together to represent an alkylene chain or alkylene chain viaan oxygen atom, a sulfur atom or a (C₂ -C₃)alkyl-substituted nitrogenatom to form, together with the adjacent nitrogen atom, a substituted orunsubstituted 3- to 7-membered cyclic amino group which may containdouble bond(s) in its ring, a substituted or unsubstituted guanidylgroup of the formula (3): ##STR4## wherein R₇ represents a hydrogen atomor an alkyl group having 1 to 3 carbon atoms, a protected or unprotectedhydroxyl group, an alkoxy group having 1 to 3 carbon atoms, anunsubstituted or (C₁ -C₃)alkyl-substituted hydrazino group or a group ofthe formula (4):

    --NHOR.sub.8                                               ( 4)

wherein R₈ represents a hydrogen atom, a protecting group for a hydroxylgroup or an alkyl group having 1 to 3 carbon atoms, and apharmacologically acceptable salt thereof, and a process for producingthe same.

DETAILED DESCRIPTION OF THE INVENTION

In the above-described formula (I), the protecting group for a hydroxylgroup as represented by R₁ and the protecting group for an amino groupas represented by R₂ may be any of those commonly employed. Preferredexamples of these protecting groups include a lower alkoxycarbonylgroup, e.g., t-butyloxycarbonyl, etc.; a halogenoalkoxycarbonyl group,e.g., 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, etc.; anaralkyloxycarbonyl group, e.g., benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, etc.; and a trialkylsilyl grouup, e.g.,trimethylsilyl, t-butyldimethylsilyl, etc.

The protecting group for a carboxyl group as represented by R₃ may beany of those commonly employed and preferably includes, for example, astraight or branched chain lower alkyl group, e.g., methyl, ethyl,isopropyl, t-butyl, etc.; a halogeno lower alkyl group, e.g.,2-iodoethyl, 2,2,2-trichloroethyl, etc.; a lower alkoxymethyl group,e.g., methoxymethyl, ethoxymethyl, isobutoxymethyl, etc.; a loweraliphatic acyloxymethyl group, e.g., acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl, etc.; a 1-loweralkoxycarbonyloxyethyl group, e.g., 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl, etc.; an aralkyl group, e.g., p-methoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, etc.; a benzhydryl group and a phthalidylgroup.

When X is a (C₁ -C₃)alkyl-substituted or unsubstituted methylene groupas represented by the formula (1), the (C₁ -C₃) alkyl group includes,for example, methyl, ethyl, n-propyl, etc.

When Y is an amino group represented by the formula (2), R₅ and R₆ maybe the same or different from each other. In the definition for R₅ andR₆, the alkyl group having 1 to 5 carbon atoms includes methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, etc.; the alkenyl group having 3to 4 carbon atoms includes, for example, propenyl, butenyl, etc.; thearalkyl group having 1 to 3 carbon atoms in its alkyl moiety includes,for example, a phenyl group, a substituted phenyl group, a pyridyl groupand a (C₁ -C₃) alkyl group substituted with a substituted pyridyl group,such as benzyl, substituted benzyl, phenethyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, etc.; the substituted alkyl grouphaving 1 to 5 carbon atoms includes, for example, a straight chain orbranched chain alkyl group, e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, etc., which is substituted with a hydroxyl group, a di(C₁ -C₃)alkylamino group, a carbamoyl group, a mono- or di-(C₁ -C₃)alkyl-substituted aminocarbonyl group, a protected or unprotectedcarboxyl group or a like substituent; and the pyridyl group includes2-pyridyl, 3-pyridyl and 4-pyridyl groups.

In cases where R₅ and R₆ jointly represent an alkylene chain or analkylene chain via an oxygen atom, a sulfur atom or a (C₁ -C₃)alkyl-substituted nitrogen atom to form, together with the adjacentnitrogen atom, a substituted or unsubstituted 3- to 7-membered cyclicamino group which may contain double bond(s) in its ring, the cyclicgroup amino group includes, for example, a saturated cyclic amino group,e.g., an aziridino group, an azetidino group, a pyrrolidino group, apiperidino group, etc.; an unsaturated cyclic amino group, e.g., apyrrolyl group, a 3-pyrrolinyl group, etc.; and a cyclic amino grouphaving an oxygen atom, a sulfur atom or an alkyl-substituted nitrogenatom in its ring, e.g., a morpholino group, a thiomorpholino group, anN-methylpiperazino group, etc. The substituents for these cyclic aminogroups include, for example, an alkyl group having 1 to 3 carbon atoms,a carbamoyl group, a mono- or di-(C₁ -C₃)alkyl-substituted aminocarbonylgroup, a hydroxyl group, etc.

When Y is represented by the formula (3), the guanidyl groupunsubstituted or substituted with a (C₁ -C₃) alkyl group includes aguanidyl group and a guanidyl group substituted with one to four alkylgroups, e.g., methyl, ethyl, n-propyl, isopropyl, etc., such as anN,N'-tetramethylguanidyl group.

The hydrazino group for Y includes, for example, a hydrazino group and ahydrazino group substituted with one to three alkyl groups, e.g.,methyl, ethyl, n-propyl, isopropyl, etc., such as2',2'-dimethylhydrazino, trimethylhydrazino, etc.

In cases where Y is represented by the formula (4), R₈ is a hydrogenatom, a protecting group commonly employed for protection of a hydroxylgroup or a lower alkyl group, e.g., methyl, ethyl, n-propyl, etc.

Of the compounds of the above-described formula (I), the carboxylic acidcompounds wherein the group as represented by --COOR₃ or --COY is acarboxyl group can be converted into their pharmacologically acceptablesalts, if desired. Such salts include those formed with inorganicmetals, such as lithium, sodium, potassium, calcium, magnesium, etc. andthose formed with ammonium, such as ammonium, cyclohexylammonium,diisopropylammonium, triethylammonium, etc., with a sodium salt and apotassium salt being preferred.

The preferred compounds of the formula (I) are those wherein R₁ is ahydrogen atom or a 1-hydroxyethyl group; R₂ and R₃ are both hydrogenatoms; and Y is a group represented by the formula (2-a): ##STR5##wherein R_(5-a) and R_(6-a) each represents a hydrogen atom, an alkylgroup having 1 to 5 carbon atoms, an alkenyl group having 3 to 4 carbonatoms, an aralkyl group having 1 to 3 carbon atoms in its alkyl moiety,an alkyl group having 1 to 5 carbon atoms which is substituted with ahydroxyl group, a di-(C₁ -C₃)alkylamino group, a carbamoyl group, amono- or di-(C₁ -C₃)alkyl-substituted aminocarbonyl group, a carboxylgroup, etc., or a pyridyl group, a R_(5-a) and R_(6-a) jointly representan alkylene chain or an alkylene chain via an oxygen atom, a sulfur atomor a (C₁ -C₃)alkyl-substituted nitrogen atom to form, together with theadjacent nitrogen atom, a substituted or unsubstituted 3- to 7-memberedcyclic amino group which may contain double bond(s) in the ring thereof,wherein the substituent for the cyclic amino group includes a (C₁-C₃)alkyl group, a carbamoyl group, a carboxyl group, a mono- or di-(C₁-C₃) alkyl-substituted aminocarbonyl group, a hydroxyl group, etc.; anunsubstituted or (C₁ -C₃)alkyl-substituted guanidyl group; a hydroxylgroup; an alkoxy group having 1 to 3 carbon atoms; an unsubstituted or(C₁ -C₃)alkyl-substituted hydrazino group; or a group represented by theformula (4-a):

    --NHOR.sub.8-a                                             ( 4-a)

wherein R_(8-a) represents a hydrogen atom or an alkyl group having 1 to3 carbon atoms.

The more preferred compounds of the formula (I) are those wherein R₁ isa 1-hydroxylethyl group; R₂ and R₃ are both hydrogen atoms; and Y is agroup represented by the formula (2-b): ##STR6## wherein R_(5-b) andR_(6-b) each represents a hydrogen atom, an alkyl group having 1 to 5carbon atoms, an alkenyl group having 3 to 4 carbon atoms, an aralkylgroup having 1 to 3 carbon atoms in its alkyl moiety, an alkyl grouphaving 1 to 5 carbon atoms which is substituted with a hydroxyl group, adi-(C₁ -C₃)alkylamino group, a carbamoyl group, a mono- or di-(C₁-C₃)alkyl-substituted aminocarbonyl group, a carboxyl grouup, etc., or apyridyl group, or R_(5-b) and R_(6-b) jointly represents an alkylenechain or alkylene chain via an oxygen atom, a sulfur atom or a (C₁-C₃)alkyl-substituted nitrogen atom to form, together with the adjacentnitrogen atom, a substituted or unsubstituted 3- to 7-membered cyclicamino group which may contain double bond(s) in its ring, wherein thesubstituent for the cyclic amino group includes an alkyl group having 1to 3 carbon atoms, a carbamoyl group, a hydroxyl group, etc.; anunsubstituted or (C₁ -C₃)alkyl-substituted guanidyl group; a hydroxylgroup; an alkoxy group having 1 to 3 carbon atoms, preferably a methoxygroup; an unsubstituted or (C₁ -C₃)alkyl-substituted hydrazino group; ora group represented by the formula (4-a):

    --NHOR.sub.8-a                                             ( 4-a)

wherein R_(8-a) has the same meaning as defined above.

The most preferred compounds of the formula (I) are those wherein R₁ isa 1-hydroxyethyl group; R₂ and R₃ are both hydrogen atoms; and Y is agroup represented by the formula (2-c): ##STR7## wherein R_(5-c) andR_(6-c) have either one of the following meanings:

(1) R_(5-c) represents an alkyl group having 1 to 5 carbon atoms whichmay be substituted with a carbamoyl group, a mono- or di-(C₁-C₃)alkylaminocarbonyl group, a hydroxyl group, etc., or a pyridylgroup, and R_(6-c) represents a hydrogen atom or has the same meaning asdescribed for R_(5-c) ;

(2) R_(5-c) and R_(6-c) are directly taken together to represent analkylene chain to form, together with the adjacent nitrogen atom, a 4-to 6-membered saturated cyclic amino group or a 5- to 6-memberedunsaturated cyclic amino group having double bond(s) in its ring, suchas a pyrrolinyl group, or the same saturated or unsaturated cyclic aminogroup as described above but having a substituent on its ring, such as acarbamoyl group, a hydroxyl group, etc.; and

(3) R_(5-c) and R_(6-c) jointly represent an alkylene chain via anoxygen atom or a (C₁ -C₃)alkyl-substituted nitrogen atom to form,together with the adjacent nitrogen atom, a 6-membered cyclic aminogroup.

Preferred examples of X, if positively enumerated, can include amethyl-substituted or unsubstituted methylene group represented by theformula (1-a): ##STR8## wherein R_(4-a) represents a hydrogen atom or amethyl group, with a group ##STR9## being particularly preferred.

The β-lactam compounds represented by the formula (I) according to thepresent invention are novel compounds belonging to carbapenem (i.e.,1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylic acid) derivatives orpenem (i.e., 1-azabicyclo[3.2.0]hept-2-ene-7-one-4-thia-2-carboxylicacid) derivatives.

A process for producing the compounds of the formula (I) according tothe present invention will be described below.

Of the β-lactam compounds of the formula (I), compounds represented bythe formula (IV): ##STR10## wherein R₁, R₂ and X are as defined above;R₉ represents a protecting group for a carboxyl group; and Y' representsthe group as represented by the foresaid formula (2), the group asrepresented by the aforesaid formula (3), a protected hydroxyl group, analkoxy group having 1 to 3 carbon atoms, an unsubstituted or (C₁-C₃)alkyl-substituted hydrazino group or a group represented by theformula (4'):

    --NHOR.sub.8 '                                             (4')

wherein R₈ ' represents a protecting group for a hydroxyl group or analkyl group having 1 to 3 carbon atoms, can be prepared by reacting aβ-lactam derivative represented by the formula (II): ##STR11## whereinR₁, X and R₉ are as defined above, and Z represents a reactive estergroup of an alcohol or a substituted or unsubstituted loweralkylsulfinyl group, with a mercaptan derivative represented by theformula (III): ##STR12## wherein R₂ and Y' are as defined above, in aninert solvent in the presence of a base.

The term "reactive ester group of an alcohol" herein used means a groupderived from a substituted or unsubstituted arylsulfonate, loweralkanesulfonate, halogeno-lower alkanesulfonate or diarylphosphoric acidester or a halide, i.e., an ester with a hydrogen halide, of the alcoholrepresented by the formula (II). The substituted or unsubstitutedarylsulfonate includes, for example, a benzenesulfonate, ap-toluenesulfonate, a p-nitrobenzenesulfonate, ap-bromobenzenesulfonate, etc. The lower alkanesulfonate includes, forexample, a methanesulfonate, an ethanesulfonate, etc. The halogeno-loweralkanesulfonate includes, for example, a trifluoromethanesulfonate, etc.The diarylphosphoric acid ester includes, for example, adiphenylphosphoric acid ester, etc. The halide includes, for example, achloride, a bromide, an iodide, etc. Of these reactive esters of analcohol, preferred examples are a p-toluenesulfonate, a methanesulfonateand a diphenylphosphoric acid ester.

Further, in the substituted or unsubstituted lower alkylsulfinyl group,the lower alkyl group preferably includes a straight chain or branchedchain alkyl group having 1 to 4 carbon atoms. The substituent for thesubstituted lower alkyl group can include a hydroxyl group, a loweralkoxy group having 1 to 4 carbon atoms, a lower alkoxycarbonyloxy grouphaving 2 to 5 carbon atoms, a lower alkanoyloxy group having 2 to 5carbon atoms, an amino group, a mono- or di-lower alkylamino group, alower alkanoylamino group having 2 to 5 carbon atoms, a loweralkoxycarbonylamino group having 2 to 5 carbon atoms, anaralkyloxycarbonyloxy group, an aralkyloxycarbonylamino group, etc.

The protecting group for a carboxyl group as represented by R₉corresponds to the protecting group as represented by R₃, and the samepreferred groups as enumerated for R₃ can also be applied to R₉.

Examples for the inert solvent which can be used in the above-describedreaction are dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide and mixtures thereof,with acetonitrile and dimethylformamide being preferred.

The base also used in the reaction includes various organic or inorganicbases, such as sodium carbonate, potassium carbonate, sodium hydride,potassium hydride, potassium t-butoxide, pyridine, various lutidines,4-dimethylaminopyridine, triethylamine, diisopropylethylamine and thelike, with the organic bases, e.g., diisopropylethylamine, etc., beingpreferred.

The amount of the base to be used should be enough for the reaction tosufficiently proceed and usually ranges from 1 to 2 equivalents per moleof the mercaptan derivative of the formula (III).

The mercaptan derivative (III) is used in an amount enough for thereaction to sufficiently proceed. It may be used in a large excess butusually in an amount of from 1 to 2 equivalents based on the compound ofthe formula (II).

The reaction can be carried out at a temperature ranging from about -78°C. to 60° C., preferably from -40° C. to 40° C.

After completion of the reaction, the reaction product can be isolatedby usual organochemical means.

Then, the thus obtained compound represented by the formula (IV) can besubjected, if necessary, to a reaction for removal of thehydroxyl-protecting group when R₁ is a protected hydroxyl group, areaction for removal of the amino-protecting group, a reaction forremoval of the carboxyl-protecting group R₉, a reaction for removal ofthe protecting group on Y', or an appropriate combination thereof,thereby to obtain the β-lactam compound represented by the formula (I).

The reactions for removal of the protecting groups can be carried out bygenerally known methods selected depending on the type of the protectinggroups. For example, those compounds of the formula (IV) wherein thehydroxyl-protecting group and/or the amino-protecting group in R₂ is/area halogenoalkoxycarbonyl group(s) or an aralkyloxycarbonyl group(s), andthose compounds wherein the carboxyl-protecting group is a halogenoalkylgroup, an aralkyl group or a benzhydryl group can be subjected to anappropriate reduction reaction to remove these protecting groups. Suchreduction is preferably carried out by using an organic solvent, such asacetic acid, tetrahydrofuran, methanol, etc., and zinc in case when theprotecting group to be removed is a halogenoalkoxycarbonyl group or ahalogenoalkyl group, or by catalytic reduction using a catalyst, such asplatinum or palladium-on-carbon, in case when the protecting group to beremoved is an aralkyloxycarbonyl group, an aralkyl group or a benzhydrylgroup. Solvents to be used in the catalytic reduction suitably includeorganic solvents, such as lower alcohols, e.g., methanol, ethanol, etc.;ethers, e.g., tetrahydrofuran, dioxane, etc.; and acetic acid, or mixedsolvents of these organic solvents and water or buffer solutions, suchas phosphoric acid, morpholinopropanesulfonic acid, etc. The reactioncan be conducted at a temperature of from about 0° C. to 100° C.,preferably 0° C. to 40° C., in a hydrogen atmosphere under atmosphericpressure or under pressurized conditions.

In particular, when the protecting group to be removed is ano-nitrobenzyl group or an o-nitrobenzyloxycarbonyl group, these groupscan also be removed by photo reaction.

In the compounds according to the present invention, the 5- and6-positions of the compounds of the above-described formula (I), the8-position of the compounds represented by the formula (V): ##STR13##wherein R₂, R₃, X and Y are as defined above, and R₁₀ represents ahydrogen atom or a protecting group for a hydroxyl group, the 4-positionof the compounds represented by the formula (VI): ##STR14## wherein R₁,R₂, R₃, R₄ and Y are as defined above, and R₄ is an alkyl group, and the2'- and 4'-positions in the 2-side chain of the compounds of theformulae (I), (V) and (VI) are all asymmetric carbons to form isomers.Therefore, the compounds represented by these formulae include opticalisomers and steric isomers ascribed to these asymmetric carbon atoms.Although all of these isomers are represented by a respective singleformula for the sake of convenience, the scope of the present inventionis not limited by such a single formula.

However, preferred isomers can include those having the samerelative-configuration as thienamycin at the 5-positioned carbon atom.With respect to the 8-positioned carbon atom of the formula (V), thosehaving an R-configuration are preferred. Further, with respect to the4-position of the formula (VI), those wherein the lower alkyl group asrepresented by R₄ is in a R-configuration (i.e., (4R)-compounds) arepreferred.

In addition, the 2'-substituted pyrrolidin-4'-ylthio group forms fourisomers, of which the (2'S,4'S)- and (2'R,4'R)-compounds are preferred.

Particularly preferred compounds include those, those compounds of theformula (V), wherein X is a sulfur atom or a methylene group, having a(5R,6S,8R,2'S,4'S)-configuration, those compounds of the formula (V),wherein X is an alkylated methylene group, having a (5S,6S,8R,2'S,4'S)and those compounds of the formula (VI), wherein R₁ is a 1-hydroxyethyltype substituent and R₄ is a lower alkyl group, having a(4R,5S,6S,8R,2'S,4'S)-configuration.

The isomers having the above-described steric configurations can beobtained by using the starting compounds of the formula (II) and/or(III) having the corresponding configurations.

The starting compounds (II) can be prepared according to various knownmethods. For example, the compounds represented by the formula (VII):##STR15## wherein R₄, R₉ and R₁₀ are as defined above, and Z₀ representsa reactive ester group of an alcohol, and also wherein R₄ is a hydrogenatom are known per se in (1) Japanese Patent Application OPI (Open toPublic Inspection) No. 27169/80, (2) J. Am. Chem. Soc., Vol. 103,6765-6767 (1981) and (3) J. Chem. Soc., Perkin I, 964-968 (1981), etc.,and the compounds (VII) can be obtained according to the methodsdescribed in the above-described literatures (1) to (3).

Further, the compounds (VII) can also be synthesized in accordance withthe methods described in the above-described literatures (1) to (3),etc. starting with compounds represented by the formula (a): ##STR16##wherein R₁₀ is as defined above, and Ac represents an acetyl group,which can be obtained by the method described in Tetrahedron Letters,2293-2296 (1982) or the method described in EPC Publication No. 70204.

Furthermore, the compounds (VII) can also be obtained by subjecting acompound represented by the formula (b): ##STR17## wherein DAMrepresents a di-p-anisylmethyl group, which is obtained by the methoddisclosed in EPC Publication No. 70204 to a carbon-increasing reactionsuch as Arndt-Einstert reaction and the like and then to anoxymercuration reaction and the like according to the method of EPCPublication No. 70204, thereby converting the ethenyl group into a1-hydroxyethyl group, subjecting the resulting product, if necessary, toan appropriate combination of a reaction for protecting or deprotectingthe carboxyl group and a reaction for protecting the hydroxyl group toobtain a compound represented by the formula (c): ##STR18## wherein R₁₀and DAM are as defined above, and then obtaining the compound (VII) fromthe compound (c) in accordance with the method described in JapanesePatent Application OPI No. 167964/82.

The DAM group on the nitrogen atom in the compound (c) can be removed byreacting with ceric ammonium nitrate in an inert solvent such asacetonitrile-water at 10° to 30° C. In this case, this reaction may becombined with a reaction for protecting or deprotecting the carboxylgroup and/or a reaction for protecting the hydroxyl group, if necessary.

Further, the compound of the formula (VII) wherein R₄ is an alkyl groupcan be prepared by, for example, the known method as disclosed inJapanese Patent Application OPI No. 26887/83 or analogous methodsthereof.

Compounds of the formula (VIII): ##STR19## wherein R₁₀ is as definedabove, and R₄ ⁰ represents an alkyl group having 1 to 3 carbon atoms,which can be used as a starting material for preparing the compound(VII) wherein R₄ is an alkyl group, can be produced, for example,according to the following reaction scheme: ##STR20## wherein R₄ ⁰ is asdefined above; R₁₁ represents a protecting group for a carboxyl group;and TBDMS represents a t-butyldimethylsilyl group.

The compounds of the formulae (e) and (f) can be obtained as an isomericmixture by a method described in Japanese Patent Application OPI No.73656/80 which comprises reacting(3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinoneof the formula (d) disclosed in Chem, Pharm. Bull., Vol. 29, 2899-2909(1981) with a halogenofatty acid ester represented by the formula:

    R.sub.4.sup.0 CHX'--COOR.sub.11

wherein R₄ ⁰ and R₁₁ are as defined above, and X' represents a halogenatom, in a solvent, such as an ether (e.g., tetrahydrofuran, dioxane,diethyl ether, etc.), an aromatic hydrocarbon (e.g., benzene, toluene,etc.), and the like, or a mixed solvent of these solvents and hexane inthe presence of diethylaluminium chloride and zinc.

Separation and purification of the isomers (e) and (f) can be carriedout by silica gel column chromatography.

The compounds (e) and (f) can be led to the compound (VIII) byappropriately combining reactions for protecting or deprotecting thehydroxyl group, the carboxyl group or the nitrogen atom.

One example for the production of the starting compound (VII) will beillustrated in the following reaction scheme: ##STR21## wherein R₄, R₉and R₁₀ are as defined above; R₁₀ ⁰ represents a protecting group for ahydroxyl group; and Ph represents a phenyl group.

More specifically, the compound (g) obtainable by the aforesaid methodscan be led to the compound (h) through the reaction described inJapanese Patent Application OPI No. 167964/82 or Heterocycles, Vol. 14,1305-1306 (1980).

The compound (h) is then reacted with a diazonizing agent, e.g.,carboxybenzenesulfonazide, in the presence of a base to obtain thecompound (i) as disclosed in Tetrahedron Letters, 31-34 (1980).

The compound (i) is then subjected to cyclization in the presence of ametal salt catalyst, e.g., dirhodium tetrakisacetate, or by photoreaction to obtain the compound (j).

Finally, the compound (j) is reacted with diphenylphosphoryl chloride inan inert solvent in the presence of a base such as diisopropyl ethylamine, 4-dimethylaminopyridine, etc. to obtain the compound of theformula (VII-a).

In general, the starting compound (VII-a) as prepared from the compound(j) is subsequently subjected to the reaction with various mercaptanswithout being isolated to produce carbapenem derivatives, but thestarting compound (VII-a) may be once isolated from the reaction mixtureand then reacted with the mercaptan derivative (III) to obtain thedesired compound of the formula (IV).

Optically active reactive esters, for example, the compound (VII-a), canbe obtained in the same manner as described above but starting with theβ-lactam derivative (g) having the corresponding steric configuration.

Further, of the above-described compounds of the formula (II), thecompounds, for example, of the compound (IX): ##STR22## wherein R₁ andR₉ are as defined above, and R₁₂ represents a substituted orunsubstituted lower alkyl group, can be prepared by subjecting acompound of the formula (X): ##STR23## wherein R₁, R₉ and R₁₂ are asdefined above, to S-oxidation using a mild oxidizing agent. The mildoxidizing agent includes perbenzoic acid, m-chloroperbenzoic acid,hydrogen, peroxide, selenium dioxide, sodium m-periodate and the like,with substituted perbenzoic acids, e.g., m-chloroperbenzoic acid, etc.,being preferred.

The starting compound represented by the formula (X) can be prepared byvarious methods already reported, for example, the methods as disclosedin Japanese Patent Application OPI Nos. 9034/80, 105686/80 and 81591/81.

On the other hand, the starting mercaptan derivative of the formula(III) can be prepared by various methods. For example, mercaptanderivatives (IIIa), (IIIb) and (IIIc) having a 2'S-configuration can beobtained from trans-4-hydroxy-L-proline (i) in accordance with thereaction scheme shown below: ##STR24## In the above formulae, R₅, R₆ andR₁₁ are as defined above; R₁₃ represents a protecting group for an aminogroup; and R₁₄ represents a protecting group for a thiol group.

Step A

The reaction can easily be accomplished by various known methodsgenerally employed for protecting an amino group of amino acids, forexample, a method comprising reacting with an arylmethyloxycarbonylchloride, etc. in the presence of a base, a method comprising using anS-acyl-4,6-dimethyl-2-mercaptopyrimidine, etc., and the like.

Step B

The reaction can be carried out by various methods for obtaining estersfrom carboxylic acids, for example, by reacting the carboxylic acid (ii)with various alkyl halides or aralkyl halides, etc. in the presence of abase.

Step C

The reaction can be accomplished by various known methods for convertinga hydroxyl group into a protected thiol group, for example, by a methodcomprising converting the carboxylic acid ester (iii) into an activeester of a hydroxyl group and then reacting with various thionizingreagents, e.g., thioacetic acid, thiobenzoic acid, tritylmercaptan,etc., in the presence of a base.

This step may also be conducted by reacting the alcohol derivative witha thionizing reagent, e.g., thioacetic acid, etc., in an inert solvent,e.g., tetrahydrofuran, etc., in the presence of triphenylphosphine anddiethyl azodicarboxylate.

Step D

This step can be carried out by various known methods for converting anester group into a carboxyl group, for example, alkali-hydrolysis, amethod of using trifluoroacetic acid, hydrobromic acid, etc., or areductive method of using zinc.

Step E

The reaction can be achieved by various known methods for converting acarboxyl group to an amido group, for example, by a method comprisingreacting with a halogenating agent, an acylating agent, etc. to form anactive ester derivative and then treating the resulting ester with anamine represented by the formula: ##STR25## wherein R₅ and R₆ are asdefined above.

Step F

The thiol-protecting group can be removed by various known methods fordeprotection. For example, an acyl group as the thiol-protecting groupcan be removed by alkali-hydrolysis and the like.

Step G

The reaction can be accomplished by various known oxidation methods forconverting a hydroxyl group into a carbonyl group, for example, anoxidation reaction using chromic acid-sulfuric acid, etc. in acetone.

Step H

The step can be attained by various known reduction reactions forconverting a carbonyl group to a hydroxyl group. For example, treatmentwith sodium borohydride, etc. gives a mixture of the compound (iii) andthe compound (ix) having different steric configurations at the hydroxylgroup. The production proportion of (iii) and (ix) varies depending onreaction conditions, but each compound can be isolated as a singlecompound by purification procedures, such as recrystallization,chromatography and the like.

Isomerization of the 4-hydroxyl group can be accomplished through theabove-described steps G and H, and may also be achieved throughhereinafter described steps I and J.

Steps I and J

The alcohol derivative is reacted with formic acid in an inert solvent,e.g., tetrahydrofuran, etc., in the presence of triphenylphosphine anddiethyl azodicarboxylate to form a formyloxy derivative (xiii), which isthen subjected to alkali-hydrolysis, etc. to remove the formyl group.

Step K

This step can be conducted by commonly employed various known methodsfor deprotecting amino groups, for example, a method of using an acid,e.g., trifluoroacetic acid, hydrobromic acid, etc., a reducing method ofusing zinc, lithium-liquid ammonia, etc., or a catalytically reducingmethod.

The starting mercaptan derivatives (III) to be used for the productionof the β-lactam compounds (I) wherein Y is a protected or unprotectedhydroxyl group or an alkoxy group having 1 to 3 carbon atoms can beobtained by subjecting the compound (iv) or (x) to Step F.

The 2'R-mercaptan (III) can be prepared by using cis-4-hydroxy-D-prolineas a starting compound in accordance with the above-described method forproducing 2'S-compounds, i.e., by combining various reactions describedin the production of the 2'S-compounds.

Of the novel β-lactam compounds represented by the formula (I) accordingto the present invention, those compounds in which R₁, R₂ and R₃ are allhydrogen atoms exhibit excellent antimicrobial activity against a widevariety of disease-causing bacteria including Gram positive bacteria,such as Staphylococcus aureaus, Staphylococcus epidermidis,Streptococcus pyogenes, Streptococcus faecalis, etc., and Gram negativebacteria, such as Escherichia coli, Proteus mirabilis, Serratiamarcescens, Pseudomonas aeruginosa, etc., and are useful, therefore, asantimicrobial agents. Further, these compounds have a characteristic ofexhibiting excellent antimicrobial activity againstβ-lactamase-producing strains. Other compounds according to the presentinvention are important intermediates for synthesizing theabove-mentioned compounds having antimicrobial activity.

In addition, the compounds according to the present invention are alsocharacterized in general by their high physiochemical stability andexcellent water solubility, although varying depending on the respectivecompound.

The compounds of the present invention can be used as antimicrobialagents for treating bacteria-caused infectious diseases in the form oforal preparations, such as tablets, capsules, powders, syrups, etc. ornon-oral preparations, such as intravenous injections, intramuscularinjections, rectal preparations, etc.

The dosage of the antimicrobial agent varies depending upon thesymptoms, ages, body weights, dosage forms, times of doses and the like,but usually ranges from about 100 mg to 3,000 mg per day in a singledose or several divided doses for adults. The above dose level can beincreased or decreased according to necessity.

Besides, the antimicrobial agent of the present invention can beadministered, if necessary, in combination withdehydrodipeptidase-inhibitors, e.g., sodiumZ-7-(L-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxyamido)-2-heptenoate,etc. (a series of compounds disclosed in Japanese Patent Application OPINo. 81518/81).

The present invention will now be illustrated in greater detail withreference to the following Reference Examples and Examples, but itshould be understood that these examples are given only for illustrativepurposes and are not limiting the present invention.

In Reference Examples and Examples, the following abbreviations areused:

DAM: Di-(p-anisyl)methyl group

TBDMS: t-Butyldimethylsilyl group

PNZ: p-Nitrobenzyloxycarbonyl group

PMZ: p-Methoxybenzyloxycarbonyl group

PMB: p-Methoxybenzyl group

PNB: p-Nitrobenzyl group

Ph: Phenyl group

Ac: Acetyl group

Ms: Methanesulfonyl group

tBu: t-Butyl group

Me: Methyl group

Et- Ethyl group

REFERENCE EXAMPLE 1--1 ##STR26##

6.55 g of trans-4-hydroxyl-L-proline and 7.5 ml of triethylamine weredissolved in 15 ml of water, and a solution of 15.95 g ofS-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 35 ml ofdioxane was added thereto dropwise. The resulting mixture was stirred atroom temperature for 1.5 hours and allowed to stand overnight. To thereaction mixture was added 30 ml of a 2N sodium hydroxide aqueoussolution under ice-cooling, and the resulting mixture was extracted withdiethyl ether. The ethereal layer was washed with 20 ml of a 1N sodiumhydroxide aqueous solution and combined with the alkaline aqueous layer.The combined mixture was made acidic with 100 ml of a 2N hydrochloricacid aqueous solution and extracted with ethyl acetate. The ethylacetate layer was washed with a 2N aqueous solution of hydrochloricacid, dried over sodium sulfate and distilled off to remove the solvent.The resulting crude crystals were washed with warm ethyl acetate toobtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline.

Melting Point: 134.3°-135.5° C.

IR_(max) ^(Nujol) (cm⁻¹): 3300 (br.), 1738, 1660, 1605, 1520, 1340,1205, 1172, 1070, 965.

REFERENCE EXAMPLE 1-2 ##STR27##

15.0 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and13.5 ml of triethylamine were dissolved in 150 ml of drieddimethylformamide, and 12.66 ml of p-methoxybenzyl chloride was addeddropwise to the solution under a nitroben stream, followed by stirringat 70° C. for 10 hours. The reaction mixture was diluted with 500 ml ofethyl acetate, washed with water, dried over sodium sulfate anddistilled off to remove the solvent. Recrystallization of the residuefrom diethyl ether gavetrans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzylester.

Melting Point: 83°-85° C.

IR_(max) ^(neat) (cm⁻¹): 3430, 1735, 1705, 1510, 1340, 1245, 1160.

REFERENCE EXAMPLE 1-3 ##STR28##

8.6 g oftrans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzylester and 7.86 g of triphenylphosphine were dissolved in 20 ml of driedtetrahydrofuran. To the resulting solution was added dropwise a solutionof 5.22 g of diethyl azodicarboxylate in 5 ml of dried tetrahydrofuranunder ice-cooling in a nitrogen stream, followed by stirring for 30minutes at that temperature. Thereafter, 2.28 g of thioacetic acid wasadded thereto dropwise, and the mixture was stirred for 1 hour underice-cooling and then at room temperature for 3 hours, followed byconcentration. The residue was purified by silica gel columnchromatography to obtaincis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline p-methoxybenzylester.

IR_(max) ^(neat) (cm⁻¹): 1740 (sh.), 1715, 1520, 1405, 1348, 1120.

NMR δ (CDCl₃): 2.31 (3H, s), 3.79 (3H, s), 5.10 (2H, s), 5.24 (2H, s),7.49 (2H, d, J=9.0 Hz), 8.18 (2H, d, J=9.0 Hz)ppm.

REFERENCE EXAMPLE 1-4 ##STR29##

9.76 g of cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-prolinep-methoxybenzyl ester and 4.32 g of anisole were stirred together with35 ml of trifluoroacetic acid at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to obtaincis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.

Melting Point: 107°-109° C.

IR_(max) ^(Nujol) (cm⁻¹): 1725, 1685, 1660 (sh.), 1340, 1180, 1110.

REFERENCE EXAMPLE 1-5 ##STR30##

180 mg of cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline wasdissolved in 2 ml of dried tetrahydrofuran, and 48 mg of dimethylaminehydrochloride, 78 mg of N,N-dimethylaminopyridine and 152 mg ofdicyclohexylcarbodiimide were successively added thereto, followed bystirring overnight. Any any insoluble matter was removed by filtration,the filtrate was diluted with ethyl acetate, washed successively withdilute hydrochloric acid and water, dried over sodium sulfate anddistilled off to remove the solvent. The residue was purified by silicagel chromatography to obtain(2S,4S)-cis-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine.

The above prepared compound could also be obtained by the followingmethod.

200 mg of the same starting carboxylic acid was dissolved in 1.8 ml ofdried methylene chloride, and one drop of dimethylformamide was addedthereto. 0.12 ml of oxalyl chloride was then added dropwise theretounder ice-cooling, followed by stirring at room temperature for 1 hour.The solvent was removed by distillation, and the residue was thoroughlydried in vacuo and dissolved in 1 ml of dried tetrahydrofuran. Underice-cooling, 1.2 ml of a 1M solution of dimethylamine in tetrahydrofuranwas added to the reaction mixture, followed by stirring at thattemperature for 15 minutes. To the reaction mixture was added ice-water,and the mixture was extracted with ethyl acetate. The organic layer waswashed successively with dilute hydrochloric acid and water, dried oversodium sulfate and distilled off to remove the solvent.

IR_(max) ^(neat) (cm⁻¹): 1705, 1650, 1515, 1400, 1340, 1105.

NMR δ (CDCl₃): 2.32 (3H, s), 2.97 (3H, s), 3.11 (3H, s), 5.21 (2H, s),8.18 (2H, d, J=8.5 Hz) ppm.

[α]_(D) ³⁰ +5.21° (c=0.379, acetone).

REFERENCE EXAMPLE 1-6 ##STR31##

277 mg of(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxycarbonyl-4-acetylthiopyridinewas dissolved in 1.5 ml of dried methylene chloride, and 0.15 ml ofoxalyl chloride and a catalytic amount of dimethylformamide were addedthereto, followed by stirring at room temperature for 1.5 hours. Thereaction mixture was distilled off to remove the solvent, and driedbenzene was added to the residue. The benzene was then distilled off toremove any remaining oxalyl chloride. Separately, 51 mg of pyrrole wasdissolved in 2 ml of dried tetrahydrofuran, and 0.47 ml of a 1.60mmol/ml solution of n-butyl-lithium in hexane was added thereto in anitrogen stream under ice-cooling, followed by stirring at thattemperature for 40 minutes. The resulting mixture was then added in anitrogen stream under ice-cooling to a solution of the above-describedreaction residue dissolved in 2 ml of dried tetrahydrofuran, followed bystirring for 10 minutes. The resulting reaction mixture was diluted withmethylene chloride, washed with water, dried over sodium sulfate anddistilled off to remove the solvent. The residue was purified by silicagel thin layer chromatography to obtain(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolyl)carbonyl-4-acetylthiopyrrolidine.

IR ν_(max) ^(CHCl) 3 (cm⁻¹): 1710, 1525, 1345, 1278, 1120.

NMR δ (CDCl₃): 2.33 (3H, s), 5.23 (2H, s), 6.35 (2H, d, J=2 Hz), 7.51(2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 1-7 ##STR32##

368 mg of(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxycarbonyl-4-acetylthiopyrrolidinewas dissolved in 3 ml of dried methylene chloride, and 0.3 ml of oxalylchloride and a catalytic amount of dimethylformamide were added thereto,followed by stirring at room temperature for 1.5 hours. The reactionmixture was distilled off to remove the solvent, and to the residue wasadded dried benzene. The benzene was then distilled off to remove anyremaining oxalyl chloride. Separately, 128 mg of 4-carbamoylpiperidinewas dissolved in 3 ml of dried tetrahydrofuran, and 0.25 ml ofbistrimethylsilylacetamide was added to the solution, followed bystirring for 3 hours in a nitrogen stream. Then, 101 mg of triethylaminewas added thereto, and to the resulting mixture was added in a nitrogenstream under ice-cooling a solution of the above-obtained reactionresidue dissolved in 3 ml of dried tetrahydrofuran, followed by stirringfor 15 minutes under ice-cooling. Methylene chloride was added to theresulting reaction mixture. The mixture was washed successively with asodium chloride aqueous solution, dilute hydrochloric acid, a sodiumchloride aqueous solution, a sodium bicarbonate aqueous solution and asodium chloride aqueous solution, dried over sodium sulfate anddistilled off to remove the solvent. The residue was purified by silicagel thin layer chromatography to obtain(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(4-carbamoylpiperidinyl)carbonyl-4-acetylthiopyrrolidine.

IR ν_(max) ^(CHCl) 3 (cm⁻¹): 3440, 1695, 1655, 1525, 1350, 1120.

NMR δ (CDCl₃): 2.35 (3H, s), 5.21 (2H, s), 5.93 (2H, s), 7.52 (2H, d,J=9 Hz), 8.22 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 1-8 ##STR33##

40 mg of(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidinewas dissolved in 4 ml of methanol, and 0.1 ml of a 1N sodium hydroxideaqueous solution was added thereto, followed by stirring at roomtemperature for 15 minutes. 0.11 ml of a 1N hydrochloric acid aqueoussolution was then added thereto, followed by concentration under reducedpressure. The concentrate was diluted with ethyl acetate, washed withwater, dried over sodium sulfate and distilled off to remove the solventto obtain(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine.

IR_(max) ^(neat) (cm⁻¹): 1705, 1650, 1515, 1400, 1340, 1165, 1105.

NMR δ (CDCl₃): 1.90 (1H, d, J=8 Hz), 2.97 (3H, s), 3.08 (3H, s), 5.19(2H, s), 7.48 (2H, d, J=9 Hz), 8.15 (2H, d, J=9 Hz) ppm.

In the same manner as described in Reference Example 1-5 but using thecorresponding amines, the following thioacetate derivatives shown inTable 1 were obtained.

                                      TABLE 1                                     __________________________________________________________________________     ##STR34##                                                                    Reference                                                                     Example No.                                                                          Y              Spectral Data                                           __________________________________________________________________________    1-9                                                                                   ##STR35##                                                                                    ##STR36##                                                                              1700, 1660(sh), 1520, 1405, 1345, 1115        1-10                                                                                  ##STR37##                                                                                    ##STR38##                                                                              3300, 1695, 1655, 1525, 1415, 1348, 1265,                                     1105                                                                NMRδ (CDCl.sub.3):                                                                1.13(3H, d, J=6Hz), 1.15(3H, d, J=6Hz),                                       2.34(3H,                                                                      s), 5.26(2H, s), 7.53(2H, d, J=9Hz),                                          8.21(2H, d,                                                                   J=9Hz)                                        1-11                                                                                  ##STR39##                                                                                    ##STR40##                                                                              1700, 1652, 1518, 1400, 1342, 1110            1-12                                                                                  ##STR41##                                                                                    ##STR42##                                                                              3320, 1680, 1520, 1430, 1405, 1345, 1120                            NMRδ (CDCl.sub.3):                                                                2.32(3H, s), 5.17(2H, br, s), 7.43(2H, d,                                     J=9Hz)                                                                        8.10(2H, d, J=9Hz)                                                            m.p. 163-167° C.                       1-13                                                                                  ##STR43##                                                                                    ##STR44##                                                                              3400(br), 1685, 1640(sh), 1517, 1403,                                         1342, 1212 1115                                                     NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 2.97(3H, s), 5.20(2H, s),                                        7.49(2H,                                                                      d, J=9Hz), 8.19(2H, d, J=9Hz)                 1-14                                                                                  ##STR45##                                                                                    ##STR46##                                                                              1710, 1660, 1525, 1400, 1345, 1255, 1110                            NMRδ (CDCl.sub.3):                                                                2.28(3H, s), 2.30(6H, s), 2.50(3H, s),                                        5.17 (2H,                                                                     s), 7.42(2H, d, J=8.5Hz), 8.13(2H, d,                                         J=8.5Hz)                                      1-15                                                                                  ##STR47##                                                                                    ##STR48##                                                                              3320, 1700, 1650, 1520, 1405, 1345, 1200                            NMRδ (CDCl.sub.3):                                                                2.33(3H, s, 2.93(3H, s), 5.23(2H, s), 7                                       bt, s)                                        1-16                                                                                  ##STR49##                                                                                    ##STR50##                                                                              1710, 1650, 1525, 1425, 1345, 1245, 1065                            NMRδ (CDCl.sub.3):                                                                1.58(6H, m), 2.32(3H, s), 5.22(2H, s)         1-17                                                                                  ##STR51##                                                                                    ##STR52##                                                                              1710, 1655, 1520, 1430, 1400, 1745, 1130                            NMRδ (CDCl.sub.3):                                                                2.31(3H, s), 5.20(2H, s), 7.47(2H, d,                                         8.18(2H, d, J=9Hz)                            1-18                                                                                  ##STR53##                                                                                    ##STR54##                                                                              1700, 1650(sh), 1520, 1435, 1340, 1290,                                       1235, 1110, 1000                              1-19                                                                                  ##STR55##                                                                                    ##STR56##                                                                              1710, 1650, 1520, 1350, 1110                                        NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 4.68(1H, t, J=8Hz), 5.19(2H,                                     s),                                                                           8.18(2H, d, J=8Hz)                            1-20                                                                                  ##STR57##                                                                                    ##STR58##                                                                              3320, 1700, 1660, 1170, 1110 m.p.                                             147-149° C.                            1-21                                                                                  ##STR59##                                                                                    ##STR60##                                                                              1705, 1690, 1520, 1345, 1160, 1110                                  NMRδ (CDCl.sub.3):                                                                2.32(3H, s), 5.22(2H, s), 7.50(2H, d,                                         J=8.5Hz),                                                                     8.19(2H, d, J=8.5Hz)                          1-22                                                                                  ##STR61##                                                                                    ##STR62##                                                                              3310, 1710, 1635, 1520, 1170, 1120 m.p.                                       200-206° C.                            1-23                                                                                  ##STR63##                                                                                    ##STR64##                                                                              3400, 1700, 1665, 1525, 1345, 1120                                  NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 7.50(2H, d, J=9Hz), 8.20(2H,                                     d,                                                                            J=9Hz)                                        1-24                                                                                  ##STR65##                                                                                    ##STR66##                                                                              3400, 3300, 3220, 1700, 1655, 1180, 1110                                      m.p. 203-209° C.                       1-25                                                                                  ##STR67##                                                                                    ##STR68##                                                                              3300, 1740, 1700, 1650, 1520, 1180 m.p.                                       185-188° C.                            1-26                                                                                  ##STR69##                                                                                    ##STR70##                                                                              3350, 3230, 1695, 1525, 1410, 1350                                  NMRδ (CDCl.sub.3):                                                                2.37(3H, s), 3.23(3H, s), 5.20(2H, s),                                        7.50(2H,                                                                      d, J=9Hz), 8.27(2H, d, J=9Hz)                 1-27                                                                                  ##STR71##                                                                                    ##STR72##                                                                              3350, 1690, 1660, 1520, 1340, 1120                                  NMRδ (CDCl.sub.3):                                                                2.36(3H, s), 3.21(2H, s), 5.23(2H, s),                                        6.93(1H                                                                       br.s), 7.50(2H, d, J=9Hz), 8.25(2H, d,                                        J=9Hz)                                        1-28                                                                                  ##STR73##                                                                                    ##STR74##                                                                              1700, 1650, 1520, 1340, 1110                                        NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 7.43(2H, d, J=8Hz), 8.20(2H,                                     d,                                                                            J=8Hz)                                        1-29                                                                                  ##STR75##                                                                                    ##STR76##                                                                              1695, 1655, 1525, 1427, 1342, 1250, 1110,                                     1065, 955                                                           NMRδ (CDCl.sub.3):                                                                2.32(3H, s), 5.21(2H, s), 7.48(2H, d,                                         J=8.5Hz),                                                                     8.18(2H, d, J=8.5Hz)                          1-30                                                                                  ##STR77##                                                                                    ##STR78##                                                                              3400, 1700, 1520, 1440, 1345, 1115                                  NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 8.20(2H, d, J=9Hz)                                               m.p. 150-151° C.                       1-31                                                                                  ##STR79##                                                                                    ##STR80##                                                                              3300, 1700, 1525, 1345, 1120                                        NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 5.25(2H, s), 7.47(2H, d,                                         J=9Hz),                                                                       8.58(1H, d, J=3Hz), 9.50(1H,br.s)             1-32                                                                                  ##STR81##                                                                                    ##STR82##                                                                              1705, 1655, 1520, 1430, 1400, 1342, 1112                            NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 5.20(2H, s), 7.47(2H, d,                                         J=8.5Hz)                                                                      8.17(2H, d, J=8.5Hz)                          1-33                                                                                  ##STR83##                                                                                    ##STR84##                                                                              1705, 1660, 1525, 1345, 1120                                        NMRδ (CDCl.sub.3):                                                                2.35(3H, s), 5.23(2H, s), 7.55(2H, d,                                         J=9Hz)                                        1-34                                                                                  ##STR85##                                                                                    ##STR86##                                                                              1705, 1640, 1516, 1430, 1400, 1342, 1110                            NMRδ (CDCl.sub.3):                                                                2.31(3H, s), 4.03(2H, dd, J=6 and 8Hz),                                       4.53(1H,                                                                      t, J=8Hz), 5.19(2H, s), 7.48(2H, d,                                           J=9Hz),                                                                       8.18(2H, d, J=9Hz)                            1-35                                                                                  ##STR87##                                                                                    ##STR88##                                                                              3430, 1700, 1640, 1345, 1245, 1120 m.p.                                       173-175° C.                            1-36                                                                                  ##STR89##                                                                                    ##STR90##                                                                              3400, 1700, 1650, 1525, 1345, 1120                                  NMRδ (CDCl.sub.3):                                                                2.33(3H, S), 5.17(2H, s), 7.47(2H, d,                                         J=9Hz),                                                                       8.18(2H, d, J=9Hz)                            1-37                                                                                  ##STR91##                                                                                    ##STR92##                                                                              1700, 1640, 1520, 1400, 1335, 1100                                  NMRδ (CDCl.sub. 3):                                                               2.33(3H, s), 5.22(2H, s), 7.50(2H, d,                                         J=9Hz),                                                                       8.20(2H, d, J=9Hz)                            1-38                                                                                  ##STR93##                                                                                    ##STR94##                                                                              1710, 1640, 1525, 1345, 1120                                        NMRδ (CDCl.sub.3):                                                                2.35(3H, s), 5.25(2H, s), 7.53(2H, d,                                         J=9Hz),                                                                       8.23(2H, d, J=9Hz)                            1-39                                                                                  ##STR95##                                                                                    ##STR96##                                                                              1700, 1610, 1520, 1400, 1350, 1110                                  NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 2.87(6H, s), 2.95(6H, s),                                        5.25(2H,                                                                      s), 7.56(2H, d, J=9Hz), 8.22(2H, d,                                           J=9Hz)                                        1-40                                                                                  ##STR97##                                                                                    ##STR98##                                                                              3350, 1705, 1610, 1525, 1345, 1120                                  NMRδ (CDCl.sub.3):                                                                2.33(3H, s), 5.23(2H, s), 8.15(2H, d,                                         J=8Hz)                                        1-41   OCH.sub.3                                                                                     ##STR99##                                                                              1750, 1705, 1690, 1523, 1441, 1352, 1226,                                     1170, 1114 m.p. 92-93.5° C.            1-42   OC.sub.2 H.sub.5                                                                              ##STR100##                                                                             1748, 1712, 1692, 1524, 1440, 1348, 1223,                                     1200 m.p. 80-81.5° C.                  1-43   NHNH.sub.2                                                                                    ##STR101##                                                                             3200, 1720, 1615, 1520, 1350, 1125 m.p.                                       208-213° C.                            1-44   NHN(CH.sub.3).sub.2                                                                           ##STR102##                                                                             3200, 1710, 1660, 1520, 1340, 1175 m.p.                                       158-159° C.                            1-45                                                                                  ##STR103##                                                                                   ##STR104##                                                                             1715, 1670, 1520, 1340, 1110                                        NMRδ (CDCl.sub.3):                                                                2.32(3H, s), 5.18(2H, s)                      1-46   NHOPNB                                                                                        ##STR105##                                                                             3200, 1730, 1700, 1680, 1520, 1340, 1120                                      m.p. 166-167° C.                       1-47   NHOCH.sub.3                                                                                   ##STR106##                                                                             3240, 1705, 1690, 1520, 1340, 1175 m.p.                                       178-179° C.                            1-48                                                                                  ##STR107##                                                                                   ##STR108##                                                                             1695, 1595, 1520, 1340, 1180, 1110                                  NMRδ (CDCl.sub.3):                                                                2.34(3H, s), 5.31(2H, s), 7.42(2H, d,                                         J=6Hz),                                                                       8.48(2H, d, J=6Hz)                            1-49                                                                                  ##STR109##                                                                                   ##STR110##                                                                             1695, 1600, 1520, 1340, 1110                                        NMRδ (CDCl.sub.3):                                                                2.34(4H, s), 2.39(3H, s), 5.18(2H, s),                                        7.48(2H,                                                                      d, J=8.5Hz), 8.21(2H, d,                      __________________________________________________________________________                                    J=8.5Hz)                                  

REFERENCE EXAMPLE 2-1 ##STR111##

3.10 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and1.10 g of triethylamine were dissolved in 40 ml of driedtetrahydrofuran, and a solution of 1.20 g of ethyl chloroformate in 10ml of dried tetrahydrofuran was added dropwise thereto at -25° C. to-35° C. After stirring at the same temperature for 50 minutes, 10 ml ofconcentrated aqueous ammonia was added dropwise to the mixture at -25°to -40° C. The temperature was then gradually elevated to roomtemperature, and the reaction mixture was stirred for 1 hour, followedby concentration under reduced pressure. To the residue were added 20 mlof water and 50 ml of diethyl ether. After ice-cooling, the thus formedwhite crystals were separated by filtration, washed successively withcool water and cool diethyl ether, and dried under reduced pressure toyield trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide.

Melting Point: 163.3°-164.0° C.

IR_(max) ^(Nujol) (cm⁻¹): 3460, 3370, 3200, 1687, 1640, 1621, 1539,1341, 1180, 1078.

REFERENCE EXAMPLE 2-2 ##STR112##

A solution of 1.89 g of methanesulfonyl chloride in 10 ml of driedtetrahydrofuran was added dropwise to a suspension of 2.32 g oftrans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 gof triethylamine in 40 ml of dried tetrahydrofuran at room temperature.After stirring for 1 hour, the reaction mixture was concentrated underreduced pressure, and to the residue were added 30 ml of water and 30 mlof diethyl ether. After cooling, the resulting white crystals wereseparated by filtration, washed successively with cool water and cooldiethyl ether and dried under reduced pressure to obtaintrans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamide.

Melting Point: 149.5°-151° C.

IR_(max) ^(Nujol) (cm⁻¹): 3400, 3225, 1715, 1675, 1520, 1340, 1170,1135.

REFERENCE EXAMPLE 2-3 ##STR113##

A solution of 642 mg of thioacetic acid in 14 ml of drieddimethylformamide was added to a suspension of 374 mg of 50% sodiumhydride in 13 ml of dried dimethylformamide in a nitrogen stream,followed by stirring at room temperature for 25 minutes. To the mixturewere added 975 mg of sodium iodide and then a solution of 2.52 g oftrans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamidein 12 ml of dried dimethylformamide, and the resulting mixture washeated to 70° C. for 6 hours while stirring. The reaction mixture waspoured into a cool aqueous solution of sodium chloride and extractedwith benzene. The extract was washed successively with a 10% aqueoussolution of sodium sulfate and a sodium chloride aqueous solution, driedover sodium sulfate and distilled off to remove the solvent. Theresulting crude crystals were washed with a warm mixed solvent oftetrahydrofuran and benzene to obtaincis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-prolineamide.

Melting Point: 168.5°-169.5° C.

IR_(max) ^(Nujol) (cm⁻¹): 3350, 3180, 1715, 1690, 1638, 1510, 1330,1100.

[α]_(D) ³⁰ -23° (c=0.334, DMF).

REFERENCE EXAMPLE 2-4 ##STR114##

950 mg of(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidinewas dissolved in 95 ml of methanol, and 2.59 ml of a 1N aqueous solutionof sodium hydroxide was added thereto at room temperature in an argonstream, followed by stirring at that temperature for 15 minutes. Thereaction mixture was neutralized with 2.59 ml of a 1N aqueous solutionof hydrochloric acid and distilled off under reduced pressure to removethe methanol. The thus precipitated crystals were filtered and washedwith water to obtain(2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine.

Melting Point: 158°-162° C.

REFERENCE EXAMPLE 3-1 ##STR115##

A soluton of 0.35 ml of dimethyl sulfoxide in 1 ml of dried methylenechloride was added dropwise to a solution of 0.2 ml of oxalyl chloridein 5 ml of dried methylene chloride at -60° to -70° C. Ten minuteslater, 10 ml of a dried methylene chloride solution of 860 mg oftrans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzylester was added dropwise to the above mixture at a temperature of -50°C. or less, followed by stirring for 15 minutes. 1.01 g of triethylaminewas then added dropwise thereto, and the resulting mixture was warmed toroom temperature. The mixture was diluted with methylene chloride,washed with dilute hydrochloric acid aqueous solution and dried oversodium sulfate. The solvent was removed by distillation, and the residuewas purified by silica gel column chromatography to yield1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester.

IR_(max) ^(neat) (cm⁻¹): 1762, 1740, 1710, 1512, 1345, 1245, 1155.

NMR δ (CDCl₃): 3.78 (3H, s), 3.95 (2H, s), 5.08 (2H, s), 6.85 (2H, d,J=9 Hz), 8.12 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 3-2 ##STR116##

650 mg of 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzylester was dissolved in 45 ml of ethanol, and 86 mg of sodium borohydridewas added thereto in two divided portions at room temperature. After 30minutes, the reaction mixture was concentrated under reduced pressure at30° C. or below, and the concentrate was diluted with ethyl acetate,washed with water, dried over sodium sulfate and distilled off to removethe solvent. The residue was purified by silica gel columnchromatography to obtaincis-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzylester (450 mg) andtrans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzylester (190 mg).

Trans-compound: The IR and NMR data were consistent with those obtainedfor the compound of Reference Example 1-2.

Cis-compound: IR_(max) ^(neat) (cm⁻¹): 3400 (br.), 1725, 1515, 1405,1350, 1250, 1170, 1120. NMR δ (CDCl₃): 3.78 (3H, s), 5.08 (2H, s), 6.82(2H, d, J=9 Hz), 8.12 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 3-3 ##STR117##

In the same manner as described in Reference Examples 1-3 and 1-4 butusing 610 mg of cis-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinep-methoxybenzyl ester,trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline was obtained.

REFERENCE EXAMPLE 3-4 ##STR118##

(a) In the same manner as described in Reference Example 1-5 but using180 mg of trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline, 100mg of(2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1700, 1655, 1515, 1400, 1340, 1115.

[α]_(D) ³⁰ +32.8° (c=0.375, acetone).

(b) In the same manner as described in Reference Example 1-8 but using80 mg of the thioacetate derivative prepared as in (a) above,(2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1700, 1650, 1510, 1420, 1400, 1340, 1120.

NMR δ (CDCl₃): 1.77 (1H, d, J=7 Hz), 2.97 (3H, s), 3.16 (3H, s), 5.22(2H, s), 8.16 (2H, d, J=8.5 Hz) ppm.

In the same manner as described in Reference Example 3-4 but using thecorresponding amines, the following thioacetates and mercaptans as shownin Table 2 were obtained.

                                      TABLE 2                                     __________________________________________________________________________     ##STR119##                                                                   Reference                                                                     Example No.                                                                          B Y     Spectral Data                                                  __________________________________________________________________________    3-5    Ac                                                                              NH.sub.2                                                                            IRν.sub.max.sup.neat (cm.sup.-1): 3300(br), 1700(sh),                      1685, 1512, 1430, 1400, 1345,                                                 1175, 1115                                                                    [α].sub.D.sup.30 + 7.36° (c=0.625, acetone)              H NH.sub.2                                                                            IRν.sub.max.sup.neat (cm.sup.-1): 1700, 1685, 1515,                        1435, 1400, 1342, 1118                                                        NMRδ (CDCl.sub.3): 2.26(1H, d, J=7Hz), 5.22(2H, s),                     8.11(2H, d,                                                                   J=8.5Hz)                                                       3-6    Ac                                                                               ##STR120##                                                                         IRν.sub.max.sup.KBr (cm.sup.-1): 1705, 1645, 1517,                         1435, 1400, 1340, 1115 NMRδ (CDCl.sub.3): 2.33(3H,                      s), 5.22(2H, s), 8.16(2H, d, J=9Hz)                                   H                                                                                ##STR121##                                                                         IRν.sub.mas.sup.neat (cm.sup.-1): 1705, 1640, 1515,                        1430, 1110                                                     __________________________________________________________________________

REFERENCE EXAMPLE 4-1 ##STR122##

166 mg of cis-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-prolinep-methoxybenzyl ester, which was obtained from cis-4-hydroxy-D-prolinein the same manner as in Reference Examples 1-1 and 1-2, and 202 mg oftriphenylphosphine were dissolved in 1.5 ml of dried tetrahydrofuran,and 27 mg of formic acid was added to the solution. 134 mg of diethylazodicarboxylate further added thereto at room temperature in a nitrogenstream. After stirring for 30 minutes, the solvent was removed bydistillation. The residue was purified by silica gel chromatography toobtain trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-prolinep-methoxybenzyl ester.

IR_(max) ^(neat) (cm⁻¹): 1720, 1515, 1402, 1342, 1245, 1165, 1120.

NMR δ (CDCl₃): 3.76 (3H, s), 4.50 (2H, t, J=8 Hz), 5.08(2H, s), 5.15(2H, ABq., J=16 Hz), 5.41 (1H, m), 7.97 (1H, s), ppm.

REFERENCE EXAMPLE 4-2 ##STR123##

215 mg of trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-prolinep-methoxybenzyl ester was dissolved in 1.1 ml of tetrahydrofuran, and0.93 ml of a 1N aqueous solution of sodium hydroxide was added to theresulting solution. After stirring for 10 minutes, the reaction mixturewas diluted with ethyl acetate, washed with a saturated aqueous solutionof sodium chloride, dried over sodium sulfate and distilled off toremove the solvent. The resulting residue was purified by silica gelthin layer chromatography to obtaintrans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline p-methoxybenzylester.

IR_(max) ^(neat) (cm⁻¹): 3425 (br.), 1735, 1705, 1510, 1400, 1340, 1240,1162.

NMR δ (CDCl₃): 2.33 (2H, m), 3.58 (2H, d, J=3.5 Hz), 3.73 (3H, s), 5.03(2H, s), 5.07 (2H, ABq., J=18 Hz), 6.73 (2H, d, J=9 Hz), 6.77 (2H, d,J=9 Hz), 8.00 (2H, d, J=8.5 Hz), 8.07 (2H, d, J=8.5 Hz) ppm.

REFERENCE EXAMPLE 4-3 ##STR124##

(a) In the same manner as described in Reference Examples 1-3, 1-4 and1-5 but using 110 mg oftrans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline p-methoxybenzylester,(2R,4R)-1-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4-acetylthiopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1705, 1650, 1515, 1435, 1340, 1115.

[α]_(D) ³⁰ -7.38° (c=0.210, acetone).

(b) In the same manner as described in Reference Example 1-8 but using42 mg of the thioacetate derivatve as obtained in (a) above,(2R,4R)-1-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4-mercaptopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1710, 1660, 1525, 1440, 1347, 1180, 1122.

REFERENCE EXAMPLE 4--4 ##STR125##

(a) In the same manner as described in Reference Examples 1-3, 1-4 and2-1 but using 110 mg oftrans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline p-methoxybenzylester, 40 mg of(2R,4R)-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-acetylthiopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1685, 1515, 1400, 1340, 1110.

[α]_(D) ³⁰ +39.6° (c=0.293, DMF).

(b) In the same manner as described in Reference Example 1-8 but using40 mg of the thioacetate derivative as obtained in (a) above,(2R,4R)-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine wasobtained.

IR_(max) ^(Nujol) (cm⁻¹): 3200, 1710, 1655, 1512, 1340, 1115.

REFERENCE EXAMPLE 5-1 ##STR126##

(a) In the same manner as described in Reference Examples 1-1, 1-2, 1-3,1-4 and 1-5 but using 300 mg of cis-4-hydroxy-D-proline, 45 mg of(2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1700, 1650, 1520, 1400, 1345, 1120.

[α]_(D) ³⁰ -29.6° (c=0.215, acetone).

(b) In the same manner as described in Reference Example 1-8 but using30 mg of the thioacetate derivative as obtained in (a) above,(2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidinewas obtained.

IR_(max) ^(neat) (cm⁻¹): 1710, 1655, 1520, 1430, 1405, 1347, 1122.

In the same manner as described in Reference Example 5-1 but using thecorresponding amines, the following thioacetate derivatives andmercaptan derivatives as shown in Table 3 were obtained.

                                      TABLE 3                                     __________________________________________________________________________     ##STR127##                                                                   Reference                                                                     Example No.                                                                          B Y     Spectral Data                                                  __________________________________________________________________________    5-2    Ac                                                                              NH.sub.2                                                                            IRν.sub.max.sup.neat (cm.sup.-1): 1705(sh), 1685, 1520,                    1425, 1402, 1342, 1122                                                        [α].sub.D.sup.30 - 6.92° (c=0.665, acetone)              H NH.sub.2                                                                            IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1695(sh),                         1682, 1515, 1395, 1340, 1115                                   5-3    Ac                                                                               ##STR128##                                                                         IRν.sub.max.sup.neat (cm.sup.-1): 1695, 1635, 1515,                        1430, 1395, 1340, 1115                                                H                                                                                ##STR129##                                                                         IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1700, 1640,                       1520, 1422, 1345, 1120                                         5-4    Ac                                                                               ##STR130##                                                                         IRν.sub.max.sup.neat (cm.sup.-1): 1700, 1655, 1620,                        1605, 1520, 1340, 1115 NMRδ (CDCl.sub.3): 2.33(3H,                      s), 5.22(2H, s), 7.49(2H, d, J=8.5Hz), 8.21(2H, d,                            J=8.5Hz)                                                                      [α].sub.D.sup.23 - 21° (c=0.25, acetone)                 H                                                                                ##STR131##                                                                         IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1705, 1660,                       1525, 1340, 1120                                               __________________________________________________________________________

REFERENCE EXAMPLE 6-1 ##STR132##

In the same manner as described in Reference Example 1-2 but using 500mg of trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline and 383 mg ofp-nitrobenzyl bromide,trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline p-nitrobenzyl esterwas obtained.

IR_(max) ^(CHCl).sbsp.3 (cm⁻¹): 3380 (br.), 1750, 1705, 1520, 1425,1400, 1342, 1160.

NMR δ(CDCl₃): 2.20 (3H, m), 3.67 (2H, d, J=3 Hz), 4.60 (2H, t, J=8 Hz),5.15 (2H, s), 5.23 (2H, ABq.), 7.47 (4H, d, J=8.5 Hz), 8.15 (4H, d,J=8.5 Hz) ppm.

REFERENCE EXAMPLE 6-2 ##STR133##

In the same manner as described in Reference Examples 1-3 and 1-8 butusing trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline p-nitrobenzylester, cis-1-p-nitrobenzyloxycarbonyl-4-mercapto-L-proline p-nitrobenzylester was obtained.

IR_(max) ^(neat) (cm⁻¹): 1700, 1685, 1600, 1510, 1430, 1400, 1340, 1105.

REFERENCE EXAMPLE 6-3 ##STR134##

(a) 115 mg of cis-1-p-nitrobenzyloxycarbonyl-4-mercapto-L-prolinep-nitrobenzyl ester was dissolved in 3 ml of dried tetrahydrofuran, and30 mg of triethylamine was added thereto. Then, 28.5 mg of ethylchloroformate was added dropwise thereto under ice-cooling, followed bystirring for 10 minutes. The reaction mixture was diluted with ethylacetate, washed successively with dilute hydrochloric acid and water,and dried over sodium sulfate. The solvent was removed by distillationto give 133 mg ofcis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-prolinep-nitrobenzyl ester.

IR_(max) ^(neat) (cm⁻¹): 1755, 1710, 1610, 1525, 1405, 1350, 1160, 1015,850.

(b) 133 mg of the thus obtained ester derivative was dissolved in 5 mlof a mixture of tetrahydrofuran and water (1:1 by volume), and 0.26 mlof a 1N aqueous solution of sodium hydroxide was added thereto. Afterstirring at room temperature for 2.5 hours, 0.3 ml of a 1N hydrochloricacid aqueous solution was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with water,dried over sodium sulfate and distilled off to remove the solvent. Theresidue was subjected to silica gel thin layer chromatography to obtaincis-1-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline.

IR_(max) ^(neat) (cm⁻¹): 1700, 1520, 1400, 1340, 1165, 1145.

NMR δ(CDCl₃): 1.30 (3H, t, J=7 Hz), 4.28 (2H, q, J=7 Hz), 5.24 (2H, s),7.50 (2H, d, J=9 Hz), 8.17 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 6-4 ##STR135##

(a) 72 mg ofcis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline wasdissolved in 3 ml of dried tetrahydrofuran, and 40 mg of triethylaminewas added thereto. Under ice-cooling, 41 mg of ethyl chloroformate wasadded dropwise thereto, followed by stirring for 15 minutes. 1.5 ml of a40% aqueous solution of methylamine was added dropwise to the mixture,followed by stirring for 15 minutes. The reaction mixture was dilutedwith ethyl acetate, washed successively with dilute hydrochloric acidand water, dried over sodium sulfate and distilled off to remove thesolvent, thereby to obtain(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylcarbamoyl-4-ethoxycarbonylthiopyrrolidine.

IR_(max) ^(Nujol) (cm⁻¹): 3290, 1705, 1660, 1520, 1425, 1405, 1345,1180, 1160.

NMR δ(CDCl₃): 1.30 (3H, t, J=8 Hz), 2.80 (3H, d, J=5 Hz), 4.27 (2H, q,J=8 Hz), 5.22 (2H, s), 7.48 (2H, d, J=9 Hz), 8.18 (2H, d, J=9 Hz) ppm.

(b) 82 mg of the methylcarbamoyl derivative as prepared in (a) above wasdissolved in 4 ml of a mixture of methanol and water (1:1 by volume),and 0.25 ml of a 1N aqueous solution of sodium hydroxide was addedthereto. After stirring at room temperature for 30 minutes, 0.27 ml of a1N hydrochloric acid aqueous solution was added thereto. The resultingmixture was extracted with ethyl acetate, and the extract was washedwith water, dried over sodium sulfate and distilled off to remove thesolvent, thereby to obtain(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylcarbamoyl-4-mercaptopyrrolidine

IR_(max) ^(Nujol) (cm⁻¹): 3280, 1710, 1650, 1510, 1340, 1165.

NMR δ(CDCl₃): 2.79 (3H, d, J=5 Hz), 4.27 (2H, t, J=8 Hz), 5.23 (2H, s),7.50 (2H, d, J=9 Hz), 8.20 (2H, d, J=9 Hz) ppm.

In the same manner as described in Reference Example 6-4(a) but usingthe corresponding amines, the following thiocarbonates as shown in Table4 were obtained.

                                      TABLE 4                                     __________________________________________________________________________     ##STR136##                                                                   Reference                                                                     Example No.                                                                          Y           Spectral Data                                              __________________________________________________________________________    6-5                                                                                   ##STR137## IRν.sub.max.sup.neat (cm.sup.-1): 3350, 1705, 1520,                        1405, 1345, 1170, 1150 NMRδ (CDCl.sub.3):                               1.27(3H, t, J=7Hz), 4.23(2H, q, J=7Hz), 5.18(2H, s),                          7.44(2H, d, J=9Hz), 8.13(2H, d, J=9Hz)                     6-6                                                                                   ##STR138## IRν.sub.max.sup.neat (cm.sup.-1): 1710, 1520, 1400,                        1345, 1170, 1148 NMRδ (CDCl.sub.3): 1.28(3H, t,                         J=7Hz), 2.19(6H, s), 4.24(2H, q, J=7Hz), 5.20(2H, s),                         7.47(2H, d, J=9Hz), 8.13(2H, d, J=9Hz)                     __________________________________________________________________________

The following mercaptans as shown in Table 5 were obtained in the samemanner as described in Reference Example 1-8 or 6-4(b).

                                      TABLE 5                                     __________________________________________________________________________     ##STR139##                                                                   Reference                                                                     Example No.                                                                          Y              Spectral Data                                           __________________________________________________________________________    7-1                                                                                   ##STR140##    IRν.sub.max.sup.neat (cm.sup.-1): 1705, 1640,                              1520, 1430, 1400, 1345, 1105                            7-2                                                                                   ##STR141##    IRν.sub.max.sup.neat (cm.sup.-1): 3290, 1710,                              1650, 1520, 1403, 1340                                  7-3                                                                                   ##STR142##    IRν.sub.max.sup.neat (cm.sup.-1): 3290, 1717,                              1660, 1520, 1410, 1350                                  7-4                                                                                   ##STR143##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3420, 3300,                             1700(sh), 1675, 1640, 1510, 1340                        7-5                                                                                   ##STR144##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3270, 1710,                             1650, 1505, 1340 NMRδ (CDCl.sub.3): 5.20(2H,                            s), 7.49(2H, q, J=8.5Hz), 8.16(2H, d, J=8.5Hz)          7-6                                                                                   ##STR145##    IRν.sub.max.sup.neat (cm.sup.-1): 3400, 1690,                              1640, 1515, 1405, 1345                                  7-7                                                                                   ##STR146##    IRν.sub.max.sup.neat (cm.sup.-1): 1705, 1650,                              1515, 1400, 1340                                        7-8                                                                                   ##STR147##    IRν.sub.max.sup.neat (cm.sup.-1): 1710, 1645,                              1520, 1440, 1345, 1245, 1025                            7-9                                                                                   ##STR148##    IRν.sub.max.sup.neat (cm.sup.-1): 1710. 1655,                              1520, 1430, 1405, 1342, 1112                            7-10                                                                                  ##STR149##    IRν.sub.max.sup.neat (cm.sup.-1): 1710, 1650,                              1520, 1405, 1345, 1205                                  7-11                                                                                  ##STR150##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3300, 1725,                             1660, 1520, 1345, 1110                                  7-12                                                                                  ##STR151##    IRν.sub.max.sup.neat (cm.sup.-1): 3280,                                    1730(sh), 1710, 1645, 1510, 1340                        7-13                                                                                  ##STR152##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3320, 1725,                             1640, 1520, 1405, 1345                                  7-14                                                                                  ##STR153##    NMRδ (CDCl.sub.3): 1.87(1H, d, J=7Hz),                                  2.96(3H, s), 2.98(3H, s), 4.33(1H, t, J=7.5Hz),                               5.24(2H, s), 7.48(2H, d, J=9Hz), 8.18(2H, d,                                  J=9Hz)                                                  7-15                                                                                  ##STR154##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3300, 1700,                             1680, 1655, 1520, 1345                                  7-16                                                                                  ##STR155##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3310, 1722,                             1650, 1525, 1350                                        7-17                                                                                  ##STR156##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3325, 1710,                             1640, 1520, 1345                                        7-18                                                                                  ##STR157##    IRν.sub.max.sup.neat (cm.sup.-1): 3350(br),                                1690, 1660(sh), 1520, 1405, 1345                        7-19                                                                                  ##STR158##    IRν.sub.max.sup.neat (cm.sup.-1): 3370, 1700,                              1665, 1525, 1410, 1350                                  7-20                                                                                  ##STR159##    IRν.sub.max.sup.neat (cm.sup.-1): 3500, 1710,                              1660, 1520, 1405, 1345                                  7-21                                                                                  ##STR160##    IRν.sub.max.sup.neat (cm.sup.-1): 3245, 1700,                              1645, 1520, 1340, 1190, 1165, 1107, 1065, 950, 850      7-22                                                                                  ##STR161##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 3410,                             1710, 1525, 1440, 1345, 1305                            7-23                                                                                  ##STR162##    IRν.sub.max.sup.Nujol (cm.sup.-1): 3250, 1710,                             1670, 1525, 1345, 1175                                  7-24                                                                                  ##STR163##    IRν.sub.max.sup.neat (cm.sup.-1): 1710, 1650,                              1518, 1435, 1400, 1345, 1170, 1110                      7-25                                                                                  ##STR164##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1710,                             1660, 1520, 1345, 1170, 1110                            7-26                                                                                  ##STR165##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1720,                             1525, 1470, 1340, 1170, 1110                            7-27                                                                                  ##STR166##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1):                                   3470(br), 1700, 1640, 1520, 1340, 1120                  7-28                                                                                  ##STR167##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1):                                   3420(br), 1700, 1645, 1520, 1340, 1165                  7-29                                                                                  ##STR168##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1710,                             1640, 1525, 1345, 1170, 1015                            7-30                                                                                  ##STR169##    NMRδ (CDCl.sub.3): 1.95(1H, d, J=8Hz),                                  5.25(2H, s), 7.52(2H, d, J=9Hz), 8.21(2H, d,                                  J=9Hz)                                                  7-31                                                                                  ##STR170##    IRν.sub.max.sup.neat (cm.sup.-1): 1705, 1600,                              1520, 1400, 1340, 1160                                  7-32                                                                                  ##STR171##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 3420,                             1695, 1610, 1522, 1350, 1110                            7-33   OCH.sub.3      IRν.sub.max.sup.neat (cm.sup.-1): 1745, 1710,                              1605, 1520, 1430, 1400, 1345, 1205,                                           1167, 1110                                              7-34   OC.sub.2 H.sub.5                                                                             IRν.sub.max.sup.neat (cm.sup.-1): 1740, 1710,                              1522, 1430, 1402, 1342, 1200, 1170,                                           1110                                                    7-35   NHNH.sub.2     IRν.sub.max.sup.Nujol (cm.sup.-1): 3180, 3050,                             1720, 1615, 1520, 1350                                  7-36   NHN(CH.sub.3).sub.2                                                                          IRν.sub.max.sup.Nujol (cm.sup.-1): 3205, 1720,                             1660, 1520, 1345, 1180                                  7-37                                                                                  ##STR172##    IRν.sub.max.sup.neat (cm.sup.-1): 1706, 1662,                              1520, 1340, 1165, 1105                                  7-38   NHOPNB         IRν.sub.max.sup.Nujol (cm.sup.-1): 3200, 1715,                             1665, 1515, 1345, 1170                                  7-39   NHOCH.sub.3    IRν.sub.max.sup.Nujol (cm.sup.-1): 3200, 1715,                             1670, 1520, 1340, 1170                                  7-40                                                                                  ##STR173##    IRν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1690,                             1650, 1525, 1405, 1345, 1170, 1110                      7-41                                                                                  ##STR174##    IRν.sub.max.sup.neat (cm.sup.-1): 1700, 1520,                              1400, 1340, 1200, 1160, 1105                            7-42                                                                                  ##STR175##    IRν.sub.max.sup.neat (cm.sup.-1): 1708, 1645,                              1520, 1440, 1405, 1350, 1170, 1115                      7-43                                                                                  ##STR176##    IRν.sub.max.sup.neat (cm.sup.-1): 1700, 1600,                              1515, 1105                                              __________________________________________________________________________

REFERENCE EXAMPLE 8-1 ##STR177##

In the same manner as described in Reference Example 1-1 but using 10 gof trans-4-hydroxy-L-proline and 23.2 g ofS-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine,trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.

IR_(max) ^(neat) (cm⁻¹): 3400 (br.), 1692, 1430, 1355, 1245, 1170, 1122.

NMR δ(CDCl₃): 2.23 (2H, m), 3.73 (3H, s), 5.00 (2H, s), 6.78 (2H, d, J=9Hz), 7.20 (2H, d, J=9 Hz) ppm.

(b) In the same manner as described in Reference Example 2-1 but using0.57 g of the proline derivative as prepared in (a) above and 0.215 g ofbenzylamine,trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolineamide wasobtained.

IR_(max) ^(Nujol) (cm⁻¹): 3375, 3300, 1665, 1248, 1165, 1120, 1025.

NMR δ(CDCl₃): 3.76 (3H, s), 4.35 (4H, m), 4.96 (2H, s), 6.79 (2H, d, J=9Hz), 7.20 (5H, s) ppm.

(c) In the same manner as described in Reference Example 1-3 but using0.5 g of the benzylprolineamide as prepared in (b) above,(2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidinewas obtained.

IR_(max) ^(Nujol) (cm⁻¹): 3280, 1690, 1675, 1240.

NMR δ(CDCl₃): 2.27 (3H, s), 3.82 (3H, s), 4.42 (2H, d, J=6 Hz), 5.05(2H, s), 6.87 (2H, d, J=8 Hz), 7.23 (2H, d, J=8 Hz), 7.28 (5H, s) ppm.

REFERENCE EXAMPLE 8-2 ##STR178##

177 mg of(2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidineand 86 mg of anisole were dissolved in 0.5 ml of trifluoroacetic acid,followed by stirring at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure, diluted with ethylacetate, washed successively with an aqueous solution of sodiumbicarbonate and water and dried over sodium sulfate. The solvent wasremoved by distillation, and the residue was subjected to silica gelthin layer chromatography to obtain(2S,4S)-2-benzylcarbamoyl-4-acetylthiopyrrolidine.

IR_(max) ^(neat) (cm⁻¹): 3325, 1690, 1510, 1400, 1350, 1120, 950.

NMR δ(CDCl₃): 2.28 (3H, s), 3.83 (2H, m), 4.42 (2H, d, J=6 Hz), 7.32(5H, s) ppm.

REFERENCE EXAMPLE 9-1 ##STR179##

7 g of 1-di-p-anisylmethyl)-3-ethenyl-4-carboxy-2-azetidinone wasdissolved in 50 ml of dried methylene chloride, and 0.8 ml ofdimethylformamide was added to the resulting solution. 2 ml of oxalylchloride was added dropwise thereto under ice-cooling, followed bystirring at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure, and to the concentrate was added 50ml of dried methylene chloride, followed by concentration again underreduced pressure. The resulting residue was dried in vacuo and thendissolved in 100 ml of dried diethyl ether. The resulting solution wasadded dropwise under ice-cooling to 120 ml of a 0.17M solution ofdiazomethane in diethyl ether to which 4 ml of triethylamine had beenadded, followed by stirring at the same temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate, washed successivelywith a 1N aqueous solution of hydrochloric acid and water, dried oversodium sulfate and distilled of to remove the solvent. The resultingoily residue was purified by silica gel chromatography to obtain1-(di-p-anisylmethyl)-3-ethenyl-4-diazoacetyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 2110, 1755, 1640, 1612, 1505, 1240, 1177, 1030,828.

NMR δ(CDCl₃): 3.78 (6H, s), 5.00 (1H, s), 5.80 (1H, s), 6.84 (4H, d,J=8.5 Hz) ppm.

REFERENCE EXAMPLE 9-2 ##STR180##

0.7 g of 1-(di-p-anisylmethyl)-3-ethenyl-4-diazoacetyl-2-azetidinone wasdissolved in 300 ml of methylene chloride, and 1 ml of water was addedthereto. The mixture was irradiated with light for 1 hour using a highpressure mercury lamp while removing oxygen from the system underice-cooling. Then, the mixture was extracted with a 1N aqueous solutionof sodium hydroxide. The aqueous layer was rendered acidic withhydrochloric acid and extracted with ethyl acetate. The extract waswashed with water, dried over sodium sulfate and distilled off to removethe solvent thereby obtaining1-(di-p-anisylmethyl)-3-ethenyl-4-carboxymethyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): ˜3000, 1700, 1612, 1510, 1300, 1180, 1030, 820.

NMR δ(CDCl₃): 2.35 (2H, d, J=6 Hz), 3.73 (6H, s), 5.80 (1H, s), 6.78(4H, d, J=9.0 Hz), 7.08 (4H, d, J=9.0 Hz) ppm.

REFERENCE EXAMPLE 9-3 ##STR181## 2.3 g of1-(di-p-anisylmethyl)-3-ethenyl-4-carboxymethyl-2-azetidinone wasdissolved in 50 ml of dried dimethylformamide, and 1.5 ml oftriethylamine was added thereto. 1.3 g of p-methoxybenzyl chloride wasthen added dropwise to the mixture, followed by stirring at 70° C. for 3hours. The reaction mixture was diluted with ethyl acetate and diethylether, washed successively with dilute hydrochloric acid and water,dried over sodium sulfate and distilled off to remove the solventthereby obtaining1-(di-p-anisylmethyl)-3-ethenyl-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 1750, 1612, 1510, 1250, 1175, 1033.

NMR δ(CDCl₃): 2.36 (2H, d, J=6.5 Hz), 3.72 (6H, s), 3.75 (3H, s), 4.83(2H, s), 5.78 (1H, s) ppm.

REFERENCE EXAMPLE 9-4 ##STR182##

2.85 g of1-(di-p-anisylmethyl)-3-ethenyl-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinonewas dissolved in 14 ml of tetrahydrofuran, and 7 ml of water and 2.0 gof mercury (II) acetate were added thereto, followed by stirring at 35°C. for 5 hours. 12 ml of a 1N aqueous solution of sodium hydroxide wasadded thereto at 0° C., and to the resulting mixture was then addeddropwise a solution of 0.25 g of sodium borohydride in 1 ml of a 1Naqueous solution of sodium hydroxide. After stirring at the sametemperature for 15 minutes, the reaction mixture was neutralized with a2N hydrochloric acid aqueous solution. Diethyl ether was added thereto,followed by filtration using Celite. The filtrate was extracted withdiethyl ether, and the extract was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate and distilled offto remove the solvent, thereby to obtain 2.6 g of1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 3430, 1730, 1615, 1510, 1247, 1178, 1030, 820.

NMR δ (CDCl₃): 1.23 (3H, d, J=6.5 Hz), 2.42 (2H, d, J=7 Hz), 3.77 (9H,s), 4.95 (2H, s), 5.78 (1H, s) ppm.

REFERENCE EXAMPLE 9-5 ##STR183##

2.6 g of1-(di-p-anisylmethyl)-3-(1hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinonewas dissolved in 15 ml of dried methylene chloride, and 1.22 g of4-dimethylaminopyridine was added thereto. Under ice-cooling, a solutionof 1.3 g of p-nitrobenzyl chloroformate in 7 ml of dried methylenechloride was added dropwise to the mixture, followed by stirring at roomtemperature for 1 hours. To the reaction mixture were added methylenechloride and water, and the methylene chloride layer was washedsuccessively with a 1N hydrochloric acid aqueous solution, water, a 5%aqueous solution of sodium bicarbonate and water, and dried over sodiumsulfate. The solvent was removed by distillation, and the residue waspurified by silica gel chromatography to obtain 2.2 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 1755, 1610, 1510, 1350, 1245, 1175, 1030.

NMR δ (CDCl₃): 1.35 (3H, d, J=6.5 Hz), 2.40 (2H, d, J=6.5 Hz), 3.09 (1H,dd, J=2.5 and 6 Hz), 3.73 (6H, s), 3.77 (3H, s), 4.91 (2H, s), 5.18 (2H,s), 5.71 (1H, s) ppm.

REFERENCE EXAMPLE 9-6 ##STR184##

2.2 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinonewas dissolved in 20 ml of dried methylene chloride, and 0.88 g ofm-dimethoxybenzene and 2.5 ml of trifluoroacetic acid were added to thesolution, followed by stirring at room temperature for 4 hours. Thesolvent was removed by distillation, and the resulting oily residue wassubjected to silica gel chromatography to obtain 1.75 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): ˜3000, 1745, 1615, 1510, 1250, 1180, 1035.

NMR δ (CDCl₃): 1.35 (3H, d, J=6.5 Hz), 2.35 (2H, d, J=6.5 Hz), 3.10 (1H,m), 3.73 (6H, s), 5.16 (2H, s), 5.75 (1H, s), 6.73 (4H, d, J=9 Hz), 7.46(2H, d, J=9 Hz), 8.10 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 9-7 ##STR185##

0.8 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinonewas dissolved in 20 ml of dried methylene chloride, and 0.17 ml ofN-methylmorpholine was added thereto. After cooling to -10° C. or less,0.15 ml of ethyl chloroformate was added dropwise thereto, followed bystirring for 30 minutes. Separately, 0.81 g of t-butyl-(p-nitrobenzyl)malonate was dissolved in 15 ml of dried tetrahydrofuran, and 0.14 g ofsodium hydride (50% purity) was added to the resulting solution in anitrogen stream under ice-cooling, followed by stirring at thattemperature for 30 minutes. The resulting solution was added dropwise tothe above prepared solution of a mixed anhydride at a temperature of-10° C. or less, followed by stirring for 1 hour. The reaction mixturewas warmed to room temperature and concentrated under reduced pressure.The concentrate was diluted with cool water and ethyl acetate, washedsuccessively with a 1N aqueous solution of hydrochloric acid and water,dried over sodium sulfate and distilled off to remove the solvent. Theresulting residue was purified by silica gel chromatography to obtain1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 1750, 1610, 1510, 1345, 1250.

NMR δ (CDCl₃): 1.38 (9H, s), 3.75 (6H, s), 5.17 (4H, s), 5.77 (1H, br.s), 6.77 (4H, d, J=8.5 Hz), 7.45 (4H, d, J=9 Hz), 8.15 (4H, d, J=9 Hz)ppm.

REFERENCE EXAMPLE 9-8 ##STR186##

2.3 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinonewas dissolved in 120 ml of dried methylene chloride, and 10 ml oftrifluoroacetic acid was added to the solution, followed by stirring atroom temperature for 1 hour. The reaction mixture was washed with anaqueous solution of sodium bicarbonate and then with water, dried oversodium sulfate and distilled off to remove the solvent. The residue waspurified by silica gel chromatography to obtain1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 1748, 1720 (sh.), 1610, 1510, 1345, 1250.

NMR δ (CDCl₃): 1.41 (3H, d, J=6.5 Hz), 2.61 (2H, d, J=6.5 Hz), 3.27 (2H,s), 3.76 (6H, s), 5.77 (1H, s), 6.82 (4H, d, J=9 Hz), 7.47 (2H, d, J=9Hz), 7.53 (2H, d, J=9 Hz), 8.20 (4H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 9-9 ##STR187##

1.9 g of1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinoneand 660 mg of p-carboxybenzenesulfonyl azide were dissolved in 50 ml ofdried acetonitrile, and 1.4 ml of trietylamine was added theretodropwise in a nitrogen stream under ice-cooling. After stirring at thattemperature for 15 minutes, the reaction mixture was diluted with ethylacetate, and the thus formed precipitate was filtered. The filtrate wasconcentrated under reduced pressure, and the resulting oily residue wassubjected to silica gel chromatography to obtain1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycaronyloxyethyl)-4-[3-p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 2150, 1750, 1720 (sh.), 1650, 1510, 1250, 1350.

NMR δ (CDCl₃): 1.38 (3H, d, J=6.5 Hz), 2.95 (2H, d, J=6.5 Hz), 3.73 (6H,s), 5.17 (2H, s), 5.24 (2H, s), 5.74 (1H, s), 6.71 (2H, d, J=9 Hz), 6.76(2H, d, J=9 Hz), 7.08 (2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 7.42 (4H,d, J=9 Hz), 8.11 (2H, d, J=9 Hz), 8.16 (2H, d, J=9 Hz) ppm.

REFERENCE EXAMPLE 9-10 ##STR188##

1.27 g1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinonewas dissolved in 50 ml of acetonitrile-water (9:1 by volume), and 2.7 gof ceric ammonium nitrate was added thereto all at once underice-cooling. After vigorously stirring, the mixture was further stirredat room temperature for 30 minutes. Cool water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with water and dried over sodium sulfate. The solvent wasdistilled off, and the resulting residue was purified by silica gelchromatography to obtain3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.

IR_(max) ^(neat) (cm⁻¹): 2145, 1750, 1720, 1650, 1520, 1345, 1260.

NMR δ (CDCl₃): 1.45 (3H, d, J=6.5 Hz), 3.01 (1H, dd, j=9 and 18 Hz),3.29 (1H, dd, J=4.5 and 18 Hz), 4.00 (1H, m), 5.24 (2H, s), 5.36 (2H,s), 6.12 (1H, s), 7.55 (4H, d, J=8.5 Hz), 8.21 (2H, d, J=8.5 Hz), 8.25(2H, d, J=8.5 Hz) ppm.

REFERENCE EXAMPLE 9-11 ##STR189##

(a) 0.55 g of3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinonewas dissolved in 25 ml of degassed dried benzene, and a catalytic amountof rhodium (II) acetate was added thereto. After blowing nitrogen gasinto the mixture for about 3 minutes, the mixture was refluxed for 20minutes, followed by cooling. The catalyst was separated by filtrationand washed with benzene. The filtrate and the washing were combined andconcentrated under reduced pressure to yieldp-nitrobenzyl-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1770, 1745, 1520, 1350, 1260.

NMR δ (CDCl₃): 1.50 (3H, d, J=6.5 Hz), 2.50 (1H, dd, J=8.0 and 18 Hz),2.89 (1H, dd, J=7.0 and 18 Hz), 3.39 (1H, dd, J=2.0 and 8.0 Hz), 4.14(1H, dt, J=2.0 and 7.0 Hz), 4.77 (1H, s), 5.26 (4H, s), 7.52 (4H, d,J=8.5 Hz), 8.21 (4H, d, J=8.5 Hz) ppm.

(b) The keto ester derivative as obtained in (a) above was dissolved in25 ml of dried acetonitrile, and 195 mg of diisopropylethylamine wasadded thereto under ice-cooling. To the resulting mixture was addeddropwise a solution of 300 mg of diphenyl chlorophosphate in 2 ml ofdried acetonitrile, followed by stirring for 1 hour. The reactionmixture was diluted with ethyl acetate, washed with water, and driedover magnesium sulfate. The solvent was removed by distillation underreduced pressure to obtain ap-nitrobenzyl-5,6-trans-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1780, 1745, 1585, 1517, 1480, 1345, 1295, 1255,1180, 1158, 965.

NMR δ (CDCl₃): 1.46 (3H, d, J=6.5 Hz), 3.24 (2H, br. d, J=8.5 Hz), 3.40(1H, dd, J=3.0 and 8.5 Hz), 5.24 (2H, s), 5.32 (2H, ABq, J=13 Hz), 7.28(10H, s), 7.53 (4H, d, J=8.5 Hz), 8.14 (2H, d, J=8.5 Hz), 8.23 (2H, d,J=8.5 Hz) ppm.

Further, by using(3R,4S)-1-(di-p-anisylmethyl)-3-ethenyl-4-carboxy-2-azetidinone [opticalrotation [α]_(D) ²² =+63.3° (c=0.12, CHCl₃)],(5R,6S,8R)-p-nitrobenzyl-3-diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxybonyloxyethyl)-1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylatewas obtained.

REFERENCE EXAMPLE 10-1 ##STR190##

To 1.33 g (20 mM) of activated zinc was added 20 ml of driedtetrahydrofuran, and 8.8 ml of a 15% n-hexane solution ofdiethylaluminium chloride was added thereto in a nitrogen stream underice-cooling. A solution prepared by dissolving 1.49 g (5.2 mM) of(3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone(1) and 3.73 g (15.3 mM) of benzyl α-bromopropionate in 13.3 ml of driedtetrahydrofuran was added dropwise to the mixture over a period of 30 to40 minutes, followed by stirring for 1 hours. Under ice-cooling, 2.8 mlof pyridine, 13.2 ml of water, 26.5 ml of ethyl acetate and 13.2 ml of a1N hydrochloric acid aqueous solution were successively added thereto,and the resulting mixture was filtered using Celite. The filtrate waswashed with water, and the organic layer was dried over sodium sulfateand distilled off to remove the solvent. The resulting oily residue wassubjected to silica gel column chromatography to obtain an isomericmixture of4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone.

The isomeric mixture was separated into each compound by Lober columnchromatography using silica gel and 1.5% isopropanol/n-hexane as aneluent to obtain the compound (2a) and the compound (2b) as oilysubstances.

Isomer (2b)

IR_(max) ^(neat) (cm⁻¹): 1755, 1460, 1377, 1252, 1100, 835.

NMR δ (CDCl₃): 0.06 (6H, s), 0.87 (9H, s), 1.16 (3H, d, J=6.5 Hz), 1.19(3H, d, J=7.0 Hz), 3.71 (1H, dd, J=2 and 10 Hz), 5.14 (2H, s), 7.35 (5H,s) ppm.

Isomer (2a)

NMR δ (CDCl₃): 0.06 (6H, s), 0.87 (9H, s), 1.08 (3H, d, J=6.5 Hz), 1.18(3H, d, J=7.0 Hz), 3.91 (1H, dd, J=2.2 and 5.5 Hz), 4.17 (2H, q, J=6Hz), 5.12 (2H, s), 7.35 (5H, s) ppm.

REFERENCE EXAMPLE 10-2 ##STR191##

200 mg of4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyl-dimethylsilyloxy)ethyl]-2-azetidinone(2a) was dissolved in 2 ml of dried dimethylformamide. 126 mg oftriethylamine was added to the resulting solution, and then 151 mg oft-butyldimethylsilyl chloride was added thereto, followed by stirring atroom temperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, dried over sodium sulfate and purified bysilica gel chromatography to obtain4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone(3a).

IR_(max) ^(neat) (cm⁻¹): 1750, 1465, 1325, 1255, 835.

REFERENCE EXAMPLE 10-3 ##STR192##

184 mg of4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone(3a) was dissolved in 4 ml of methanol, and the resulting solution wasstirred together with 20 mg of 10% palladium-on-carbon at an atmosphericpressure of hydrogen for 2 hours. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain4-(1-carboxy)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone(4a).

IR_(max) ^(neat) (cm⁻¹): 1740, 1465, 1330, 1255, 1043, 837.

REFERENCE EXAMPLE 10-4 ##STR193##

(4R,5R,6S,8R)-p-Nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-3,7-dione-2-carboxylatewas obtained from 170 mg of4-(1-carboxy)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone(4a) according to the method described in Japanese Patent ApplicationOPI No. 26887/83, pages 64-65.

IR_(max) ^(neat) (cm⁻¹): 3450 (br.), 1770 (sh.), 1750, 1605, 1520, 1350,1217, 1180.

REFERENCE EXAMPLE 11 ##STR194##

To a solution of 261 mg of(5R,6S,8R)-p-nitrobenzyl-3-ethylthio-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-ene-7-one-4-thia-2-carboxylatein 28 ml of dried methylene chloride, 144 mg of m-chloroperbenzoic acidwas added at -45° C. in a nitrogen stream, followed by stirring at -20°to -40° C. for 2 hours. The reaction mixture was washed with a saturatedaqueos solution of sodium bicarbonate and then with water, dried oversodium sulfate and distilled off to remove the solvent. The resultingresidue was purified by silica gel chromatography to obtain(5R,6S,8R)-p-nitrobenzyl-3-ethylsulfinyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-ene-7-one-4-thia-2-carboxylate.

IRν_(max) ^(CHCl).sbsp.3 (cm⁻¹): 1793, 1703, 1605, 1517, 1447, 1377,1344, 1315, 1172, 1112, 1043, 965, 824.

NMR δ (CDCl₃): 5.74 (3/5H, d, J=1.5 Hz), 5.87 (2/5H, d, J=1.5 Hz) ppm.

EXAMPLE 1-1 ##STR195##

(a) 122 mg of(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylatewas dissolved in 3 ml of dry acetonitrile, and 31 mg ofdiisopropylethylamine was added thereto in a nitrogen stream underice-cooling. Then, 60 mg of[2S,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidinewas added to the mixture, followed by stirring for 1 hour. The reactionsolution was diluted with ethyl acetate, washed with water, dried overmagnesium sulfate and the solvent was distilled off. The residue waspurified by silica gel thin layer chromatography to obtain 95 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1780, 1745, 1705, 1650, 1605, 1515, 1342, 1257.

NMR δ(CDCl₃): 1.49 (3H, d, J=6 Hz), 2.99 (3H, s), 3.11 (3H, s), 5.25(4H, s), 5.23 and 5.46 (2H, ABq, J=14 Hz), 7.53 (4H, d, J=8.5 Hz), 7.62(2H, d, J=8.5 Hz), 8.18 (6H, d, J=8.5 Hz).

[α]_(D) ²⁸ +7.7° (c=0.303, acetone).

(b) 95 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylatewas dissolved in 20 ml of dioxane, and a morpholinopropanesulfonic acidbuffer solution (pH=7.0, 10 ml) and platinum oxide (35 mg) were addedthereto. The mixture was then hydrogenated under a hydrogen pressure of3.5 atm. for 6.5 hours. The catalyst was filtered off and dioxane wasdistilled off under reduced pressure. The residual solution was washedwith ethyl acetate, and the aqueous layer was again distilled underreduced pressure to remove the organic solvent. The residual solutionwas subjected to polymer chromatography (CHP-20P) to obtain(5R,6S,8R,2'S,4'S)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid from the fraction eluted with water.

UV_(max) ^(H).sbsp.2^(O) nm: 297.

IR_(max) ^(KBr) cm⁻¹ : 1755, 1627, 1393, 1252, 1130.

NMR δ(D₂ O): 1.25 (3H, d, J=6.4 Hz), 1.81-1.96 (1H, m), 2.96 (3H, s),3.03 (3H, s), 3.14-3.20 (3H, m), 3.31-3.41 (2H, m), 3.62-3.72 (1H, m),3.90-4.00 (1H, m), 4.14-4.26 (2H, m), 4.63 (1H, t, J=8.5 Hz).

EXAMPLE 1-2 ##STR196##

(a) In the same manner as described in Example 1-1(a) but using 129 mgof(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylateand 67 mg of[2S,4R]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine,there was obtained 40 mg of(5R,6S,8R,2'S,4'R)-p-nitrobenyl-3-[4-(1-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1775, 1745, 1705, 1650, 1520, 1400, 1345, 1260,1130.

NMR δ(CDCl₃): 1.48 (3H, d, J=6 Hz), 2.96 (3H, s), 3.12 (3H, s), 5.22(4H, s), 7.44, 7.50 and 7.58 (each 2H, d, J=8.5 Hz), 8.17 (6H, d, J=8.5Hz).

[α]_(D) ²⁷ +31.1° (c=0.193, acetone).

(b) In the same manner as described in Example 1-1(b) but using 40 mg of(5R,6S,8R,2'S,4'R)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate,there was obtained(5R,6S,8R,2'S,4'R)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid.

UV_(max) ^(H).sbsp.2^(O) nm: 297.

EXAMPLE 1-3 ##STR197##

(a) In the same manner as described in Example 1-1(a) but using 61 mg of(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylateand 31 mg of[2R,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine,there was obtained 37 mg of(5R,6S,8R,2'R,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1775, 1745, 1705, 1650, 1520, 1400, 1345, 1260,1130.

NMR δ(CDCl₃): 1.49 (3H, d, J=6.5 Hz), 2.98 (3H, s), 3.16 (3H, s), 5.27(4H, s), 5.19 and 5.47 (2H, ABq, J=14 Hz), 7.50, 7.55 and 7.64 (each 2H,d, J=8.5 Hz), 8.20 (4H, d, J=8.5 Hz), 8.22 (2H, d, J=8.5 Hz).

[α]_(D) ²⁹ +26.8° (c=0.243, acetone).

(b) In the same manner as described in Example 1-1(b) but using 37 mg of(5R,6S,8R,2'R,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate,there was obtained(5R,6S,8R,2'R,4'S)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid.

UV_(max) ^(H).sbsp.2^(O) nm: 297.

EXAMPLE 1-4 ##STR198##

(a) In the same manner as described in Example 1-1(a) but using 76 mg of(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nirobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylateand 39 mg of[2R,4R]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine,there was obtained 35 mg of(5R,6S,8R,2'R,4'R)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1775, 1745, 1705, 1650, 1520, 1440, 1342, 1260,1120.

NMR δ(CDCl₃): 1.49 (3H, d, J=6.5 Hz), 2.98 (3H, s), 3.09 (3H, s), 5.25(4H, s), 5.26 and 5.44 (2H, ABq, J=14 Hz), 8.20 (6H, d, J=8.5 Hz).

[α]_(D) ³⁰ +23.3° (c=0.329, acetone).

(b) In the same manner as described in Example 1-1(b) but using 35 mg of(5R,6S,8R,2'R,4'R)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylate,there was obtained(5R,6S,8R,2'R,4'R)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid.

UV_(max) ^(H).sbsp.2^(O) nm: 297.

EXAMPLE 2 ##STR199##

(a) 53 mg of(4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-3,7-dione-2-carboxylatewas dissolved in 5 ml of dry acetonitrile, and 57 mg ofdiisopropylethylamine and then 43 mg of diphenyl chlorophosphate wereadded thereto. After stirring for 2.5 hours, 57 mg of[2S,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidinewas added to the mixture, followed by stirring for 1 hour. The reactionsolution was diluted with ethyl acetate, washed with water, dried overmagnesium sulfate and the solvent was distilled off. The residue waspurified by silica gel thin layer chromatography to obtain 35 mg of (4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1760, 1705, 1645, 1520, 1402, 1342, 1135, 1110.

NMR δ(CDCl₃): 1.30 (3H, d, J=7.0 Hz), 1.35 (3H, d, J=6.5 Hz), 2.99 (3H,s), 3.02 (3H, d, J=15 Hz), 5.21 (2H, s), 5.20 and 5.43 (2H, ABq, J=14Hz), 7.51 (2H, d, J=8.5 Hz), 7.64 (2H, d, J=8.5 Hz), 8.20 (4H, d, J=8.5Hz).

(b) 25 mg of(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylatewas dissolved in a mixture of 1.9 ml of tetrahydrofuran and 0.3 ml ofethanol, and the mixture was hydrogenated in a morpholinopropanesulfonicacid buffer solution (pH=7.0, 1.9 ml) under atmospheric pressure ofhydrogen for 3 hours at room temperature in the presence of 30 mg of 10%palladium-carbon, which had been activated in hydrogen atmosphere for 1hour followed by washing with water. After filtering off the catalyst,tetrahydrofuran and ethanol were distilled off under reduced pressure,and the residual solution was washed with ethyl acetate. The aqueouslayer was again distilled under reduced pressure to remove organicsolvents, and the residual solution was subjected to polymerchromatography (CHP-20P) to obtain (4R,5S,6S,8R,2'S,4'S)-3-[4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid from the fraction eluted with water.

UV_(max) ^(H).sbsp.2^(O) nm: 296.

NMR δ(D₂ O): 1.21 (3H, d, J=7.0 Hz), 1.29 (3H, d, J=6.5 Hz), 1.92 (1H,m), 2.99 (3H, s), 3.06 (3H, s).

EXAMPLE 3 ##STR200##

(a) 61 mg of(4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-3,7-dione-2-carboxylatewas dissolved in 6 ml of dry acetonitrile, and 72 mg ofdiiropropylethylamine and then 55 mg of diphenyl chlorophosphate wereadded thereto in a nitrogen stream under ice-cooling, followed bystirring for 2.5 hours. 77 mg of[2S,4S]-1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)-4-mercaptopyrrolidinewas added to the mixture, followed by stirring for 1 hour. The reactionsolution was diluted with ethyl acetate, washed with water, dried overmagnesium sulfate, and the solvent was distilled off. The residue waspurified by silica gel thin layer chromatography to obtain 51 mg of(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(neat) (cm⁻¹): 1760, 1710, 1640, 1525, 1440, 1350, 1210, 1110.

NMR δ(CDCl₃): 1.30 (3H, d, J=7.0 Hz), 1.34 (3H, d, J=6.5 Hz), 5.21 (2H,s), 5.20 and 5.44 (2H, ABq, J=14 Hz), 7.50 (2H, d, J=8.5 Hz), 7.64 (2H,d, J=8.5 Hz), 8.20 (4H, d, J=8.5 Hz).

(b) 50 mg of(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylatewas dissolved in a mixture of 3.9 ml of tetrahydrofuran and 0.6 ml ofethanol, and the mixture was hydrogenated in a morpholinopropanesulfonicacid buffer solution (pH=7.0, 3.9 ml) under atmospheric pressure ofhydrogen for 4.5 hours at room temperature in the presence of 60 mg of10% palladium-carbon, which had been activated in hydrogen atmospherefor 1 hour followed by washing with water. After filtering off thecatalyst, tetrahydrofuran and ethanol were distilled off under reducedpressure, and the residual solution was washed with ethyl acetate. Theaqueous layer was again distilled under reduced pressure to removeorganic solvents, and the residual solution was subjected to polymerchromatography (CHP-20P) to obtain(4R,5S,6S,8R,2'S,4'S)-3-[2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylicacid from the fraction eluted with a 2% aqueous tetrahydrofuransolution.

UV_(max) ^(H).sbsp.2^(O) nm: 297.

NMR δ(D₂ O): 1.20 (3H, d, J=7.0 Hz), 1.28 (3H, d, J=6.5 Hz), 1.95 (6H,m), 3.46 (6H, m), 3.72 (1H, dd, J=6.5 and 12 Hz), 4.02 (1H, quintet,J=6.5 Hz).

EXAMPLE 4 ##STR201##

(a) 172 mg of(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylatewas dissolved in 2.3 ml of dry acetonitrile, and to the solution wereadded a solution of 59 mg of diisopropylethylamine in 0.7 ml of dryacetonitrile and then a solution of 94 mg of[2S,4S]-1-nitrobenzyloxycarbonyl-2-(3-pyrroline-1-carbonyl)-4-mercaptopyrrolidinein 1 ml of dry acetonitrile, in a nitrogen stream and under ice-cooling,followed by stirring for 15 minutes. The reaction solution was dilutedwith diethyl ether, washed with water, and the insoluble material in theether layer was dissolved with addition of methylene chloride. Themethylene chloride and ether layer was dried over magnesium sulfate andthe solvent was distilled off. The residue was purified by silica gelthin layer chromatography to obtain 182 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-{4-[1-p-nitrobenzyloxycarbonyl-2-(3-pyrroline-1-carbonyl)]pyrrolidinylthio}-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylate.

IR_(max) ^(CHCl).sbsp.3 (cm⁻¹): 1780, 1745, 1708, 1660, 1623, 1606,1520, 1342.

NMR δ(CDCl₃): 1.49 (3H, d, J=6.2 Hz), 5.26 (4H, s), 8.18 (6H, d, J=8.8Hz).

(b) 182 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-{4-[1-p-nitrobenzyloxycarbonyl-2-(3-pyrroline-1-carbonyl)]pyrrolidinylthio}-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-ene-7-one-2-carboxylatewas dissolved in a mixture of 12.6 ml of tetrahydrofuran and 2 ml ofethanol, and the solution was hydrogenated in amorpholinopropanesulfonic acid buffer solution (pH=7.0, 12.6 ml) at roomtemperature under atmospheric pressure of hydrogen for 7 hours in thepresence of 219 mg of 10% palladium-carbon, which had been activated inhydrogen atmosphere for 1 hour, followed by washing with water. Afterfiltering off the catalyst, tetrahydrofuran and ethanol were distilledoff under reduced pressure, and the residual solution was washed withethyl acetate. The aqueous layer was again distilled under reducedpressure to remove organic solvents, and the residual solution wassubjected to polymer chromatography (CHP-20P) to obtain(5R,6S,8R,2'S,4'S)-3-{4-[2-(3-pyrroline-1-carbonyl)]pyrrolidinylthio}-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid from the fraction eluted with a 2% aqueous tetrahydrofuransolution.

UV ν_(max) ^(H).sbsp.2^(O) nm: 298.

IR_(max) ^(KBr) (cm⁻¹): 1755, 1640, 1595, 1450, 1380, 1245.

NMR δ(D₂ O): 1.26 (3H, d, J=6.4 Hz), 3.18 (1H, dd, J=2.1 and 9.0 Hz),3.77 (1H, dd, J=7.0 and 12.0 Hz), 5.89 (2H, br. s).

EXAMPLE 5 ##STR202##

(a) Following the procedures as described in Example 1-1(a) using 68 mgof(5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylateand 33 mg of[2S,4S]-1-p-nitrobenzyloxycarbonyl-2-carbamoylmethylaminecarbonyl-4-mercaptopyrrolidine,there was obtained 61 mg of crystalline (5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-carbamoylmethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylateby filtration.

IR_(max) ^(Nujol) (cm⁻¹): 3445, 3300, 1790, 1745, 1710, 1670, 1635,1510, 1345, 1270.

NMR δ(CDCl₃): 1.50 (3H, d, J=6.5 Hz), 5.23 (4H, s), 7.50 (4H, d, J=8.5Hz), 8.21 (6H, d, J=8.5 Hz).

m.p.: 184°-189° C. (dec.).

(b) 30 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-carbamoylmethylaminecarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylatewas dissolved in a mixture of 3.1 ml of tetrahydrofuran and 1 ml ofdimethylformamide, and the solution was hydrogenated in the presence ofa morpholinopropanesulfonic acid buffer solution (pH=7.0, 3.1 ml) atroom temperature under atmospheric pressure of hydrogen for 5 hours inthe presence of 37 mg of 10% palladium-carbon which had been activatedin hydrogen atmosphere for 1 hour followed by washing with water. Afterfiltering off the catalyst, tetrahydrofuran was distilled off underreduced pressure, and the residual solution was washed with methylenechloride. The aqueous layer was distilled to remove the organicsolvents, and the residual solution was subjected to polymerchromatography (CHP-20P) to obtain(5R,6S,8R,2'S,4'S)-3-[4-(2-carbamoylmethylaminecarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylic acid from the fractioneluted with water.

UV ν_(max) ^(H).sbsp.2^(O) nm: 300.

IR_(max) ^(KBr) (cm⁻¹): 1745, 1665, 1590, 1390, 1220, 1180, 1040.

NMR δ(D₂ O): 1.26 (3H, d, J=6.6 Hz), 1.86 (1H, m), 3.20 (2H, dd, J=7.5and 14.7 Hz), 3.38 (1H, dd, J=3.0 and 6.7 Hz), 4.02 (1H, t, J=9.0 Hz).##STR203##

(a) To a solution of 45 mg of(5R,6S,8R)-p-nitrobenzyl-3-ethylsulfinyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-4-thia-2-carboxylatein 0.8 ml of dry acetonitrile were added a solution of 30 mg ofdiisopropylethylamine in 0.3 ml of dry acetonitrile and then a solutionof 81 mg of(2'S,4'S)-1'-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4'-mercaptopyrrolidinein 0.6 ml of dry acetonitrile under nitrogen stream at -40° C., followedby stirring the mixture at -40° C. to -45° C. for 10 minutes. Thereaction solution was diluted with ethyl acetate, washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and the solvent was distilled off. The resulting residue waspurified by silica gel chromatography to obtain(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-ene-7-one-4-thia-2-carboxylate.

[α]_(D) ²⁹ +52° (c=0.43, CHCl₃).

IR ν_(max) ^(CHCl) ₃ (cm⁻¹): 1788, 1700, 1660, 1607, 1400, 1325, 1114,1013.

NMR δ(CDCl₃): 1.32 (3H, d, J=6 Hz), 2.96 (3H, s), 3.08 (3H, s), 3.72(1H, dd, J=1.5 Hz and J=6 Hz), 5.20 (2H, s), 5.70 (1H, d, J=1.5 Hz).

204 mg of 5% palladium-carbon was suspended in a mixture of ethanol (3.8ml) and water (3.8 ml) and hydrogenated at room temperature underatmospheric pressure for 1 hour. The catalyst was filtered, washed withwater, suspended in a phosphate buffer (pH=6.86, 5.1 ml), and added to asolution of 68 mg of(5R,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-4-thia-2-carboxylatein 7.7 ml of tetrahydrofuran. The mixture was hydrogenated at roomtemperature and under atmospheric pressure for 3 hours. After filteringoff the catalyst, tetrahydrofuran was distilled off under reducedpressure. The residual solution was washed with ethyl acetate, and theaqueous layer was again distilled under reduced pressure to remove theorganic solvents. The resulting residual solution was purified byCHP-20P column chromatography to obtain(5R,6S,8R,2'S,4'S)-2-[(2-dimethylaminecarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-4-thia-2-carboxylicacid.

UV λ_(max) ^(H).sbsp.2^(O) nm: 322, 255.

IR ν_(max) ^(KBr) (cm⁻¹): 1765, 1645, 1580, 1508, 1367.

NMR δ(D₂ O): 1.29 (3H, d, J=6.4 Hz), 1.94-2.08 (1H, m), 2.93-3.15 (1H,m), 2.98 (3H, s), 3.05 (3H, s), 3.53-3.62 (1H, m), 3.83-3.93 (1H, m),3.94 (1H, dd, J=1.4 Hz and J=6 Hz), 4.06-4.30 (3H, m), 5.71 (1H, d,J=1.4 Hz).

EXAMPLES 7 TO 90

The compounds shown in Table 6 below were prepared from thecorresponding mercaptan derivatives. In Table 6, "HE" represents(R)-1-hydroxyethyl group, and "PNZE" represents(R)-1-p-nitrobenzyloxycarbonyloxyethyl group.

                                      TABLE 6                                     __________________________________________________________________________    Ex-                                                                           am-                                                                           ple                                                                           No.                                                                              R.sub.1                                                                           R.sub.2                                                                          R.sub.3                                                                          Y              Spectral Data                                     __________________________________________________________________________     ##STR204##                                                                      PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR205##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       3420, 1785, 1742, 1710, 1677,                                                 1510, 1342, 1255                                                              m.p. 138-142° C.                                                       [α].sub.D.sup.30                                                        +44.4° (c=0.105, DMF)                                    UVλ.sub.max.sup.H.sbsp.2.sup.O nm: 297     7  HE  H  H                                                                                 ##STR206##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1752, 1687, 1595, 1385                                          NMRδ (D.sub.2 O):                                                                     1.24(3H, d, J=6.5Hz),                                                         2.0-2.15(1H,                                                                  m), 2.83-2.98(1H, m), 3.17(2H,                                                d,                                                                            J=9Hz), 3.32-3.42(2H, m),                                                     3.71-                                                                         3.80(1H, m), 3.98(1H, quintet;                                                J=7Hz), 4.13-4.32(1H, m),                                                     4.41(1H, t,                                                                   J=8.5Hz)                                                                      [α].sub.D.sup.30                                                        -25° (c=0.05, H.sub.2                                                  O)                                  8  PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR207##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775, 1745, 1700, 1665(sh),                                                   1515 1345, 1257                                                 NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 2.73(3H,                                                s),                                                                           3.21(2H, d, J=9Hz), 5.25(4H,                                                  s),                                                                           5.25 and 5.43(2H, ABq,                                                        J=14Hz),                                                                      7.50, 7.54 and 7.62(each 2H,                                                  d,                                                                            J=8.5Hz), 8.20(6H, d, J=8.5Hz)         HE  H  H                                                                                 ##STR208##    UVλ.sub.max.sup.H.sbsp.2.sup.O nm: 297     9  PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR209##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1770, 1740, 1700, 1510, 1340,                                                 1255                                                            NMRδ(CDCl.sub.3):                                                                     1.08(3H, d, J=6.5Hz), 1.11(3H,                                                d,                                                                            J=6.5Hz), 1.48(3H, d, J=6Hz),                                                 3.18(2H, br.d, J=9Hz), 5.25(4H,                                               s),                                                                           5.26 and 5.44(2H, ABq,                                                        J=14Hz),                                                                      7.50, 7.54 and 7.62(each 2H,                                                  J=9Hz), 8.20(6H, d, J=8.5Hz)           HE  H  H                                                                                 ##STR210##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       296                                    PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR211##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       3275, 1782, 1740, 1700, 1650,                                                 1515 1340, 1260                                                 NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 3.18(2H,                                                br,                                                                           d, J=9Hz), 5.24(4H, s), 5.25                                                  and                                                                           5.45(2H, ABq, J=14Hz), 7.50,                                                  7.53                                                                          and 7.62(each 2H, d, J=8.5Hz),                                                8.19(6H, d, J=8.5Hz)                10 HE  H  H                                                                                 ##STR212##    NMRδ (D.sub.2 O):                                                                     1.0(3H, t, J=7.5Hz), 1.23(3H,                                                 d, J=7Hz)                                                       UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR213##    NMRδ (D.sub.2 O):                                                                     1.27(3H, d, J=7Hz), 5.68(3H,                                                  m)                                                              UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                 11 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR214##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1750, 1710, 1650, 1525,                                                 1440 1350, 1262                                                 NMRδ (CDCl.sub.3):                                                                    1.06(3H, t, J=7Hz), 1.27(3H,                                                  t,                                                                            J= 7Hz), 1.49(3H, d, J=6Hz),                                                  5.24(4H,                                                                      s), 5.25 and 5.46(2H, ABq,                                                    J=14Hz),                                                                      7.46, 7.50 and 7.63(each 2H,                                                  d,                                                                            J=8.5Hz), 8.20(6H, d, J=8.5Hz)         HE  H  H                                                                                 ##STR215##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                    PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR216##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1746, 1708, 1656, 1610,                                                 1525, 1350, 1260                                                NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6Hz), 5.27(4H,                                                  s),                                                                           8.20(6H, d, J=9Hz)                                              UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                 12 HE  H  H                                                                                 ##STR217##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1635, 1590, 1370, 1240                                    NMRδ (D.sub.2 O):                                                                     0.88(3H, t, J=7.1Hz), 1.26(3H,                                                d,                                                                            J=6.4Hz), 1.91(1H, m), 2.94                                                   and                                                                           3.02(3H, s)                         13 PNZE                                                                              H  PNB                                                                               ##STR218##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1770, 1735, 1640, 1510, 1340,                                                 1250                                                            NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.5Hz), 4.42(2H,                                                d,                                                                            J=7.0Hz), 5.25(4H, s), 5.27                                                   and                                                                           5.43(2H, ABq, J=14Hz), 7.27(5H,                                               s),                                                                           7.54, 7.62, 8.21 and 8.22(each                                                2H,                                                                           d, J=8.5Hz)                            HE  H  H                                                                                 ##STR219##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                                             IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1750, 1715, 1660, 1525,                                                 1442,                                                                         1350, 1265, 1122                    14 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR220##    NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 2.92(3H,                                                s), 4.56(2H, d, J=5Hz),                                                       5.25(4H, s), 8.19(6H, d,                                                      J=9Hz)                                 HE  H  H                                                                                 ##STR221##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                    PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR222##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1790, 1745, 1714, 1652, 1605,                                                 1520 1347 m.p. 179-182°                                                C. (dec.)                                                       UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       299, 266, 260                       15 HE  H  H                                                                                 ##STR223##    IRλ.sub.max.sup.KBr (cm.sup.-1):                                                     1745, 1590, 1490, 1210, 1090,                                                 910                                                             NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 1.99(1H,                                                m),                                                                           2.80(1H, m), 3.36(1H, dd, J=2.7                                               and                                                                           6.0Hz), 3.58(1H, dd, J=7.0 and                                                12.0Hz), 3.86(1H, m), 4.51(2H,                                                d,                                                                            J=4.4Hz), 7.82(1H, dt, J=1.8                                                  and                                                                           7.7Hz), 8.42(1H, m)                 16 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR224##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775, 1745, 1700, 1660(sh),                                                   1515 1345, 1260                                                 NMRδ (CDCl.sub.3):                                                                    1.47(3H, d, J=6.5Hz), 2.24(3H,                                                s),                                                                           2.27(3H, s), 5.25(4H, s), 7.49,                                               7.53                                                                          and 7.62(each 2H, d, J=8.5Hz),                                                8.20(6H, d, J=8.5Hz)                   HE  H  H                                                                                 ##STR225##    UVλ.sub.max.sup.H.sbsp.2.sup.O nm: 297                                 IRν.sub.max.sup.neat (cm.sup.-1):                                                        1770, 1745, 1700, 1650, 1512,                                                 1342,                                                                         1257                                17 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR226##    NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.0Hz), 2.24(3H,                                                s), 2.30(6H, s), 5.25(4H, s),                                                 5.27 and 5.45(2H, ABq,                                                        J=13.5Hz), 7.54(4H,                                                           d, J=8.5Hz), 7.63(2H, d,                                                      J=8.5Hz), 8.20(6H, d, J=8.5Hz)         HE  H  H                                                                                 ##STR227##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                 18 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR228##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        3350, 1770, 1740, 1695, 1510,                                                 1340, 1250                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6Hz), 5.25(4H,                                                  s),                                                                           5.18 and 5.43(2H, ABq,                                                        J=14Hz),                                                                      7.49, 7.53 and 7.61(each 2H,                                                  d,                                                                            J=8.5Hz), 8.18(6H, d, J=8.5Hz)         HE  H  H                                                                                 ##STR229##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                                             IRν.sub.max.sup.neat (cm.sup.-1):                                                        3400, 1778, 1745, 1700, 1650,                                                 1520,                                                                         1345, 1260, 1120                    19 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR230##    NMRδ  (CDCl.sub.3):                                                                   1.48(3H, d, J=6.5Hz), 3.00(3H,                                                s), 5.20(2H, s), 5.25(2H, s),                                                 5.25 and 5.45(2H, ABq,                                                        J=13.5Hz), 7.49, 7.51 and                                                     7.63(each 2H, d, J=8.5Hz),                                                    8.19(4H, d, J=8.5Hz), 8.21(2H,                                                d, J=8.5Hz)                            HE  H  H                                                                                 ##STR231##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                 20 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR232##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1770, 1730, 1695, 1650, 1600,                                                 1505, 1340                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 5.25(4H,                                                s),                                                                           7.62(2H, d, J=8.6Hz), 8.20(6H,                                                d,                                                                            J=8.6Hz)                               HE  H  H                                                                                 ##STR233##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                    PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR234##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1795, 1747, 1712, 1640, 1608,                                                 1517, 1350, 1275 m.p.                                                         167-169° C. (dec.)                                       UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                 21 HE  H  H                                                                                 ##STR235##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1752, 1650, 1590, 1388, 1255,                                                 1150                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 2.71(3H,                                                s),                                                                           2.93(1H, q, J=7.4Hz), 3.88(2H,                                                s)                                  22 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR236##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1800, 1750, 1707, 1675, 1650,                                                 1610, 1520, 1350, 1280 m.p.                                                   196-199° C. (dec.)                                       UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       299                                    HE  H  H                                                                                 ##STR237##    IRν.sub.max.sup.KRb (cm.sup.-1):                                                         1750, 1640, 1590, 1380, 1250,                                                 1145                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 2.92(3H,                                                s),                                                                           3.03(3H, s), 3.19(2H, dd, J=6.3                                               and                                                                           9.2Hz), 3.51(1H, dd, J=7.4 and                                                12Hz),                                                                        4.12(2H, s)                         23 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR238##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1795, 1750, 1700, 1680, 1655,                                                 1610, 1525, 1350 m.p.                                                         168-170° C. (dec.)              HE  H  H                                                                                 ##STR239##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1745, 1665, 1590, 1390, 1180,                                                 1037                                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                 24 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR240##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1790, 1752, 1710, 1650, 1610,                                                 1525, 1350 m.p. 98-101°                                                C.                                                              UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       301                                    HE  H  H                                                                                 ##STR241##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1650, 1590, 1385, 1170,                                                 1040                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.6Hz), 1.36(3H,                                                d,                                                                            J=8.1Hz), 2.71(3H, s), 3.19(1H,                                               dd,                                                                           J=6.6 and 9.0Hz), 3.98(1H, t,                                                 J=8.0Hz)                            25 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR242##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1745, 1705, 1640, 1605,                                                 1520, 1346 m.p. 172-175°                                               C.                                                              NMRδ (D.sub.6DMCO):                                                                   1.12(3H, d, J=7Hz), 1.34(3H,                                                  d,                                                                            J=6.4), 2.79(3H, s),2.94(3H,                                                  s),                                                                           5.30(2H, s), 8.20(6H, d,                                                      J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H                                                                                 ##STR243##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1630, 1590, 1390, 1250,                                                 1120                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 1.31(3H,                                                d,                                                                            J=6.9Hz), 2.92(3H,s ), 3.13(3H,                                               s)                                  26 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR244##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1783, 1746, 1705, 1680, 1608,                                                 1524, 1345                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.4Hz), 3.19(3H,                                                s),                                                                           5.17(2H, s), 5.24(2H, s),                                                     8.19(6H,                                                                      d, J=8.6Hz)                                                     UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H                                                                                 ##STR245##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1654, 1590, 1395, 1250,                                                 1060                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 2.95(3H,                                                s),                                                                           3.21(2H, dd, J=2.2 and 9.0Hz),                                                3.38(1H, dd, J=2.2 and 5.5Hz)       27 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR246##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1778, 1743, 1685, 1660, 1605,                                                 1520, 1340                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.2Hz), 2.72(3H,                                                d,                                                                            J=5Hz), 3.19(3H, s), 5.22(2H,                                                 s),                                                                           5.25(2H, s), 8.22(6H, d,                                                      J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H                                                                                 ##STR247##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1640, 1585, 1382, 1250,                                                 1125                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 2.73(3H,                                                s),                                                                           3.09(3H, s), 3.39(1H, q,                                                      J=2.6Hz)                            28 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR248##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1778, 1745, 1705, 1650, 1605,                                                 1520, 1345                                                      NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.2Hz), 2.93(3H,                                                s),                                                                           2.99(3H, s), 3.10 and 3.15(3H,                                                s),                                                                           5.25(4H, s), 8.21(6H, d,                                                      J=8.4Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                    HE  H  H                                                                                 ##STR249##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1760, 1650, 1500, 1380, 1240,                                                 1130                                29 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR250##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1778, 1750, 1705, 1650, 1518,                                                 1430, 1345, 1258                                                NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.5Hz), 2.25(3H,                                                s),                                                                           2.31(4H, s), 5.25(4H, s), 5.21                                                and                                                                           5.46(2H, ABq, J=13.5Hz),                                                      7.53(4H, d,                                                                   8.20(6H, d, J=8.5Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR251##    IRν.sub.max.sup.neat (cm.sup.-1                                                          1780, 1750, 1710, 1655, 1520,                                                 1350, 1255, 1115                    30 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR252##    NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 3.58 and                                                3.67(each 4H, s), 5.25(4H, s),                                                5.26 and 5.45(2H, ABq, J=14Hz),                                               7.53(4H, d, J=9Hz), 7.62(2H, d,                                               J=9Hz), 8.19(6H, d, J=9Hz)             HE  H  H                                                                                 ##STR253##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                 31 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR254##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1740, 1705, 1655, 1610,                                                 1520, 1345                                                      NMRδ CDC.sub.3):                                                                      1.47(3H, d, J=6Hz), 5.22(4H,                                                  s),                                                                           8.13(6H, d, J=8Hz)                                              UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR255##    IRν.sub.max.sup.KBr  (cm.sup.-1):                                                        1750, 1625, 1595, 1396, 1248,                                                 1090                                32 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR256##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1740, 1700, 1590, 1520,                                                 1340, 1255                                                      NMRδ (CDCL.sub.3):                                                                    1.49(3H, d, J=6.6Hz), 5.26(4H,                                                s),                                                                           5.35(2H, ABq, J=14.5Hz),                                                      7.46(2H, d,                                                                   J=5.5Hz), 8.48(2H, d, J=5.5Hz)                                  UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       245, 300                               HE  H  H                                                                                 ##STR257##    IRν (cm.sup.-1):                                                                         1745, 1690, 1590, 1507, 1383,                                                 1285                                33 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR258##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1785, 1745, 1705, 1605, 1520,                                                 1350 m.p. 181-183° C.                                                  (dec.)                                                          UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       296, 276, 231                          HE  H  H                                                                                 ##STR259##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1690, 1595, 1435, 1385,                                                 1240, 1090                                                      NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 1.95(1H,                                                m),                                                                           3.20(1H, dd, J=4.0 and 9.0Hz),                                                3.37(1H, dd, J=2.6 and 6.1Hz),                                                8.32(1H, dd, J=1.3 and 5.0Hz),                                                8.60(1H, d, J=2.2Hz)                34 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR260##    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1790, 1745, 1705, 1670, 1605,                                                 1515, 1345 m.p. 189-191°                                               C. (dec.)                                                       UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298, 286, 237                          HE  H  H                                                                                 ##STR261##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1680, 1590, 1480, 1390,                                                 1245, 1090                                                      NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 1.95(1H,                                                m),                                                                           3.20(1H, dd, J=4.0 and 9.0Hz),                                                3.37(1H, dd, J=2.6 and 6.1Hz),                                                8.32(1H, dd, J=1.3 and 4.9Hz),                                                8.60(1H, d, J=2.2Hz)                35 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR262##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775, 1750, 1705, 1640, 1520,                                                 1345, 1255, 1110                                                NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 5.24(4H,                                                s),                                                                           5.23 and 5.44(2H, ABq,                                                        J=14Hz),                                                                      8.19(6H, d, J=8.5Hz)                   HE  H  H                                                                                 ##STR263##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                 __________________________________________________________________________

    __________________________________________________________________________    36 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR264##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1782, 1750, 1710, 1660, 1522,                                                 1445, 1355, 1270, 1140                                          NMRδ (CDC.sub.3):                                                                     1.48(3H, d, J=6Hz), 5.26(4H,                                                  2),                                                                           5.18 and 5.42(2H, ABq,                                                        J=14Hz),                                                                      7.50(2H, d, J=8.5Hz), 7.53(2H,                                                d,                                                                            J=8.5Hz), 7.62(2H, d,                                                         J=8.5Hz),                                                                     8.19(6H, d, J=8.5Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR265##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1630, 1600, 1440, 1382,                                                 1240                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 2.34(2H,                                                m),                                                                           3.36(1H, dd, J=3.4 and 5.5Hz),                                                3.84(1H, m)                         37 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR266##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1740(sh), 1710, 1605,                                                   1520, 1340                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.4Hz), 5.25(4H,                                                s),                                                                           6.32(2H, d, J=2Hz), 8.16(6H,                                                  d,                                                                            J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297, 241                               HE  H  H                                                                                 ##STR267##    IRν.sub.max .sup.KBr (cm.sup.-1):                                                        1750, 1720, 1590, 1470, 1390,                                                 1280                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.2Hz), 2.12(2H,                                                m),                                                                           6.44(2H, t, J=2.2Hz), 7.39(2H,                                                t,                                                                            J=2.2Hz)                            38 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR268##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1750, 1700, 1650(sh),                                                   1610, 1525, 1350                                                NMRδ (CDCl.sub.3):                                                                    1.47(3H, d, J=6Hz), 5.22(4H,                                                  s),                                                                           8.12(6H, d, J=8.5Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR269##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1650, 1600, 1440, 1395        39 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR270##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1783, 1750, 1715, 1660, 1615,                                                 1530, 1350                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=5.9Hz), 5.25(4H,s                                               ),                                                                            8.15(6H, d, J=8.6Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR271##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1630, 1590, 1460, 1380,                                                 1240, 1090                                                      NMRδ (D.sub.2 O):                                                                     1.27(3H, d, J=6.3Hz), 3.19(1H,                                                dd,                                                                           J=2.9 and 9.2 Hz), 3.39(1H, dd,                                               J=2.6                                                                         and 6.0Hz)                             PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR272##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1740, 1708, 1640, 1605,                                                 1520, 1345                                                      NMRδ (CDCl.sub.3):                                                                    1.50(3H, d, J=6.2Hz), 5.28(4H,                                                s),                                                                           8.19(6H, d, J=8.1Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                 40 HE  H  H                                                                                 ##STR273##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1760, 1635, 1600, 1450, 1380                                    NMRδ (D.sub.2 O):                                                                     1.27(3H, d, J=6.3Hz), 3.19(1H,                                                dd,                                                                           J=2.9 and 9.1Hz), 3.39(1H, dd,                                                J=2.7                                                                         and 6.0Hz), 3.55(2H, d,                                                       J=4.0Hz),                                                                     3.69(1H, dd, J=2.0 and 4.3Hz)       41 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR274##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1750, 1705, 1635, 1605,                                                 1520, 1345                                                      NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.4Hz), 5.26(4H,                                                s),                                                                           8.20(6H, d, J=8.8Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR275##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1625, 1440, 1380, 1240                                    NMRδ (D.sub.2 O):                                                                     1.23(3H, d, J=6.5Hz), 1.25(3H,                                                d,                                                                            J=6Hz), 1.31(3H, d, J=7Hz)          42 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR276##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1785, 1746, 1705, 1657, 1610,                                                 1525, 1345                                                      NMRδ (CDCl.sub.3):                                                                    1.47(3H, d, J=6.2Hz), 5.25(4H,                                                s),                                                                           8.16(6H, d, J=8.6Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR277##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1655(sh), 1635, 1610(sh),                                               1380, 1220                                                      NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz)                43 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR278##    IRν.sub.mzx.sup.CHCl.sbsp.3                                                              1780, 1745, 1702, 1603, 1520,                                                 1345                                                            NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6Hz), 2.85(6H,                                                  s),                                                                           2.93(6H, s), 5.26(4H, s)                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       299,229                                HE  H  H                                                                                 ##STR279##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1690, 1590, 1420, 1285,                                                 1130                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.3Hz), 1.91(1H,                                                m),                                                                           2.60(1H, m), 3.08(6H, s),                                                     3.16(6H,                                                                      s), 3.40(1H, dd, J=2.7 and                                                    6.0Hz),                                                                       4.37(1H, dd, J=6.0 and 9.5Hz)       44 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR280##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1780, 1740, 1705, 1605, 1523,                                                 1345                                                            NMRδ (CDCl.sub.3):                                                                    1.47(3H, d, J=6.8Hz), 5.25(4H,                                                s)                                                              UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       207, 299                               HE  H  H                                                                                 ##STR281##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1640, 1590, 1545, 1385,                                                 1040                                                            NMRδ (D.sub.2 O):                                                                     1.25(3H, d, J=6.6Hz), 1.85(1H,                                                m)                                  45 PNZE                                                                              PNZ                                                                              PNB                                                                              OPNB           IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775(sh), 1750, 1710, 1520,                                                   1350,                                                                         1265                                                            NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 4.70(1H,                                                dd,                                                                           J=6 and 8.5Hz), 5.25(4H, s),                                                  5.46(1H, d, J=14Hz), 7.53(4H,                                                 d,                                                                            J=8.5Hz), 7.62(4H, d,                                                         J=8.5Hz),                                                                     8.18(4H, d, J=8.5Hz), 8.21(4H,                                                d,                                                                            J=8.5Hz)                               HE  H  H  OH             UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       294                                 46 PNZE                                                                              PNZ                                                                              PNB                                                                              OCH.sub.3      IRν.sub.max.sup.CHCl.sbsp.3                                                              1787, 1753, 1716, 1614, 1530,                                                 1431,                                                                         1410, 1355, 1268, 1138, 1116                                    NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6Hz),                                                           1.83-2.42(1H, m),                                                             2.50-3.02(1H, m), 3.17-4.53(8H,                                               m),                                                                           3.70 and 3.73(3H, s),                                                         5.02-5.28(2H,                                                                 m), 5.27(4H, s), 5.47(1H, d,                                                  J=14Hz),                                                                      7.53(4H, d, J=9Hz), 7.63(2H,                                                  d,                                                                            J=9Hz), 8.21(6H, d, J=9Hz)                                      UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H  OCH.sub.3      IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1735, 1595, 1488, 1388, 1245,                                                 1090                                __________________________________________________________________________    47 PNZE                                                                              PNZ                                                                              PNB                                                                              NHNH.sub. 2    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1782, 1750, 1705, 1620, 1520,                                                 1350                                                                          m.p. 184-187° C. (dec.)                                  UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       299                                    HE  H  H  NHNH.sub.2     IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1720, 1590, 1390, 1245,                                                 1120                                48 PNZE                                                                              PNZ                                                                              PNB                                                                              NHN(CH.sub.3).sub.2                                                                          IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1785, 1750, 1715, 1668, 1608,                                                 1520, -      1345                                                             m.p. 187-189° C. (dec.)                                  UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H  NHN(ch.sub.3).sub.2                                                                          IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1690, 1595, 1390, 1175,                                                 1020                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.4Hz), 2.60(6H,                                                s),                                                                           3.18(1H, dd, J=6.0 and 9.1Hz),                                                3.39(1H, dd, J=2.6 and 6.0Hz)       49 PNZE                                                                              PNZ                                                                              PNB                                                                              OC.sub.2 H.sub.5                                                                             IRν.sub.max.sup.CHCl.sbsp.3                                                              1784, 1750, 1714, 1608, 1524,                                                 1432,                                                                         1404, 1378, 1348, 1265, 1197,                                                 1132,                                                                         1113                                                            NMRδ (CDCl.sub.3):                                                                    1.13-1.36(3H, m), 1.48(3H, d,                                                 J=6Hz), 1.83-2.36(1H, m),                                                     2.56-                                                                         3.06(1H, m), 3.19-4.59(10H,                                                   m),                                                                           4.89-5.36(2H, m), 5.27(4H, s),                                                5.47(1H, d, J=14Hz), 7.54(4H,                                                 d,                                                                            J=8.5Hz), 7.63(2H, d,                                                         J=8.5Hz),                                                                     8.20(6H, d, J=8.5Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H  OC.sub.2 H.sub.5                                                                             IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1743, 1597, 1380, 1240, 1130                                    NMRδ (D.sub.2 O):                                                                     1.25(3H, d, J=6Hz), 1.27(3H,                                                  t,                                                                            J=7Hz), 2.29(1H, m), 4.29(2H,                                                 q,                                                                            J=7Hz)                              50 PNZE                                                                              PNZ                                                                              PNB                                                                              NHOPNB         IRν.sub.max.sup.Nujol (cm.sup.-1                                                         1790, 1750, 1715, 1670, 1602,                                                 1515,                                                                         1340                                                                          m.p. 149-152° C. (dec.)                                  UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H  NHOH           IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1680, 1600, 1400, 1120        51 PNZE                                                                              PNZ                                                                              PNB                                                                              NHOCH.sub.3    IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1787, 1745, 1710, 1665, 1605,                                                 1520                                                                          1345                                                                          m.p. 188-189.5° C.                                                     (dec.)                                                          UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       299                                    HE  H  H  NHOCH.sub.3    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1745, 1680, 1600, 1440, 1390,                                                 1245,                                                                         1050                                                            NMRδ (D.sub.2 O):                                                                     3.70(3H, s)                         52 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR282##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1773, 1743, 1705, 1663, 1605,                                                 1523, 1345, 1255                                                NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.5Hz), 5.23(2H,                                                s),                                                                           5.26(2H, s), 8.19(6H, d,                                                      J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                    HE  H  H                                                                                 ##STR283##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1763, 1660, 1590, 1380, 1240,                                                 1060                                                            NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.6Hz), 2.50(3H,                                                s),                                                                           2.52(3H, s), 2.92(3H, s),                                                     3.18(2H, q,                                                                   J=4.3Hz)                            53 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR284##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1750, 1710, 1605, 1525,                                                 1350, 1260                                                      NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.4Hz), 5.25(4H,                                                s),                                                                           5.36(2H, ABq, J=13.6Hz),                                                      7.53(4H, d,                                                                   J=8.8Hz), 7.62(2H, d,                                                         J=8.8Hz),                                                                     8.21(6H, d, J=8.8Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       300                                    HE  H  H                                                                                 ##STR285##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1735, 1595, 1396, 1255, 1215,                                                 1043                                54 PNZE                                                                              PNZ                                                                              PNB                                                                               ##STR286##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1745, 1705, 1645, 1520,                                                 1440, 1350, 1262                                                NMRδ (CDCl.sub.3):                                                                    1.49(3H, d, J=6.5Hz), 5.26(4H,                                                s),                                                                           5.24 and 5.43(2H, ABq,                                                        J=14Hz),                                                                      7.44(2H, d, J=9Hz), 7.48(2H,                                                  d,                                                                            J=9Hz), 7.68(2H, d, J=9Hz),                                                   8.19(6H,                                                                      d, J=9Hz)                              HE  H  H                                                                                 ##STR287##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                                             NMRδ (D.sub.2 O):                                                                     1.27(3H, d, J=6Hz), 1.83(4H, t,                                               J=7Hz),                                                                       1.94-2.09(1H, m), 2.42(4H, t,                                                 J=7Hz),                                                                       2.77-2.92(1H, m), 3.11-3.42(5H,                                               m),                                                                           3.81-3.99(1H, m), 4.14-                                                       4.29(2H, m)                          ##STR288##                                                                   Ex-                                                                           am-                                                                           ple                                                                           No.                                                                              R.sub.1                                                                              R.sub.3                                                                          A                            Spectral Data                       __________________________________________________________________________    55 PNZE   PNZ                                                                               ##STR289##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775, 1745, 1700, 1520, 1345,                                                 1260, 1130                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 3.22(2H,                                                br,                                                                           d, J=9.0Hz), 5.26(4H, s), 5.25                                                and                                                                           5.46(2H, ABq, J=14Hz), 7.50,                                                  7.54                                                                          and 7.60(each 2H, d, J=9.0Hz),                                                8.18(4H, d, J=9.0Hz), 8.21(2H,                                                d,                                                                            J=9.0Hz)                                                        [α].sub.D.sup.29 +37.3°                                                        (c=0.244, acetone)                     HE     H                                                                                 ##STR290##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       298                                 56 PNZE   PNZ                                                                               ##STR291##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1780, 1745, 1700, 1610, 1520,                                                 1400, 1350, 1260, 1120                                          NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6Hz), 3.19(2H,                                                  d,                                                                            J=9Hz), 3.44(1H, dd, J=2.5 and                                                7.5Hz), 5.25(4H, s), 5.23 and                                                 5.42(2H, ABq, J=14Hz), 7.47,                                                  7.52 and                                                                      7.60(each 2H, d, J=8.5Hz),                                                    8.16(4H,                                                                      d, J=8.5Hz), 8.19(2H, d,                                                      J=8.5Hz)                                                        [α].sub.d.sup.32 +57.6°                                                        (c=0.279, acetone)                     HE     H                                                                                 ##STR292##    UVλ.sub.mx.sup.H.sbsp.2.sup.O                                                        297                                 57 PNZE   PNB                                                                               ##STR293##    IRν.sub.max.sup.neat (cm.sup.-1):                                                        1775, 1750, 1700, 1520, 1345,                                                 1260, 1180                                                      NMRδ (CDCl.sub.3):                                                                    1.48(3H, d, J=6.5Hz), 3.26(2H,                                                br,                                                                           d, J=9.0Hz), 5.25(4H, s), 5.18                                                and                                                                           5.46(2H, Abq, J=14Hz), 7.49,                                                  7.53                                                                          and 7.62(each 2H, d, J=8.5Hz),                                                8.17(4H, d, J=8.5Hz), 8.19(2H,                                                d,                                                                            J=8.5Hz)                                                        [α].sub.d.sup.25 +43.7°                                                        (c=0.353, acetone)                     HE     H                                                                                 ##STR294##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                 58 PNZE   PNB                                                                               ##STR295##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1750, 1705, 1645, 1610, 1525,                                                 1440, 1350, 1265                       HE     H                                                                                 ##STR296##    UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       287                                 __________________________________________________________________________     ##STR297##                                                                   __________________________________________________________________________

    __________________________________________________________________________    59 HE  PNZ                                                                              PNB                                                                              NH.sub.2       IRν.sub.max.sup.CHCl.sbsp.3                                                              1775, 1700, 1607, 1520, 1395,                                                 1345,                                                                         1105                                                            NMRδ (CDCl.sub.3):                                                                    1.36(3H, d, J=6.0Hz), 1.37(3H,                                                d,                                                                            J=7.0Hz), 5.24(2H, s), 5.35(2H,                                               N                                                                             ABq, J=13.5Hz), 7.50(2H, d,                                                   J=8.8Hz), 7.64(2H, d,                                                         J=8.8Hz),                                                                     8.22(4H, d, J=8.8Hz)                                            UVλhd max.sup.H.sbsp.2.sup.O                                                         295                                    HE  H  H  NH.sub.2       IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1660(sh), 1600, 1380,                                                   1240                                60 HE  PNZ                                                                              PNB                                                                               ##STR298##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1770, 1695, 1650, 1520, 1340                                    NMRδ (CDCl.sub.3):                                                                    1.34(3H, d, J=6.15Hz), 1.36(3H,                                               d,                                                                            J=8.0Hz), 3.00(3H, s), 5.20(2H,                                               s),                                                                           5.36(2H, ABq, J=14.0Hz),                                                      7.47(2H,                                                                      d, J=8.8Hz), 7.64(2H, d,                                                      J=8.8Hz),                                                                     8.20(2H, d, J=8.8Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       289                                    HE  H  H                                                                                 ##STR299##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1630, 1605, 1375, 1240        61 HE  PNZ                                                                              PNB                                                                              NHCH.sub.2 CONH.sub.2                                                                        IRν.sub.max.sup.CHCl.sbsp.3                                                              3380, 1770, 1725(sh), 1700,                                                   1680,                                                                         1605, 1520, 1342, 1250, 1102                                    NMRδ (CDCl.sub.3):                                                                    5.30(2H, s), 5.31(2H, ABq,                                                    J=13.8Hz), 7.48(2H, d,                                                        J=8.8Hz),                                                                     7.64(2H, d, J=8.8Hz), 8.21(4H,                                                d,                                                                            J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       295                                    HE  H  H  NHCH.sub.2 CONH.sub.2                                                                        IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1670, 1600, 1390, 1245                                    NMRδ (D.sub.2 O):                                                                     1.26(3H, d, J=6.5Hz), 1.28(3H,                                                d,                                                                            J=8Hz), 3.92(2H, s)                 62 HE  PNZ                                                                              PNB                                                                               ##STR300##    IRν.sub.max.sup.CHCl.sbsp.3                                                              3480, 3350, 1773, 1678, 1604,                                                 1525, 1345, 1310                                                NMRδ (CDCl.sub.3):                                                                    1.34(3H, d, J=6.2Hz), 1.37(3H,                                                d,                                                                            J=7.0Hz), 3.20(3H, s), 5.18(2H,                                               s),                                                                           5.36(2H, ABq, J=13.4Hz),                                                      7.46(2H,                                                                      d, J=8.8Hz), 7.63(2H, d,                                                      J=8.8Hz),                                                                     8.20(2H, d, J=8.8Hz), 8.21(2H,                                                d,                                                                            J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       292                                    HE  H  H                                                                                 ##STR301##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1752, 1645, 1600, 1385, 1245        63 HE  PNZ                                                                              PNB                                                                               ##STR302##    IRν.sub.max.sup.CHCl.sbsp.3                                                              3420, 1772, 1705, 1660, 1623,                                                 1606, 1526, 1440, 1345                                          [α].sub.D.sup.25 -45° (c=0.11,                                   CHCl.sub.3)                                                                   NMRδ (CDCl.sub.3):                                                                    1.33(3H, d, J=6.15Hz), 1.37(3H,                                               d,                                                                            J=6.8Hz), 4.19(4H, br, s),                                                    5.21(2H,                                                                      s), 5.36(2H, ABq, J=13.9Hz),                                                  5.84(2H, s), 7.40(2H, d,                                                      J=8.6Hz),                                                                     7.64(2H, d, J=8.6Hz), 8.14(2H,                                                d,                                                                            J=8.6Hz), 8.19(2H, d, J=8.6Hz)                                  UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       293                                    HE  H  H                                                                                 ##STR303##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1640, 1610, 1460, 1380                                    NMRδ (D.sub.2 O):                                                                     1.25(3H, d, J=6Hz), 1.27(3H,                                                  d,                                                                            J=7.5Hz), 5.85(2H, br, s)           64 HE  PNZ                                                                              PNB                                                                               ##STR304##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1770, 1702, 1650, 1520, 1343,                                                 1102                                                            NMRδ  (CDCl.sub.3):                                                                   1.33(3H, d, J=6.15Hz), 1.37(3H,                                               d,                                                                            J=7.0Hz), 5.21(2H, s), 5.36(2H,                                               ABq,                                                                          J=13.9Hz), 7.50(2H, d,                                                        J=8.6Hz),                                                                     7.64(2H, d, J=8.6Hz), 8.20(4H,                                                d,                                                                            J=8.6Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       293                                    HE  H  H                                                                                 ##STR305##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1630(sh), 1610, 1442,                                                   1383, 1240, 1110                                                NMRδ (D.sub.2 O):                                                                     1.25(3H, d, J=6.5Hz), 1.28(3H,                                                d,                                                                            J=7Hz)                              65 HE  PNZ                                                                              PNB                                                                               ##STR306##    IRν.sub.max.sup.CHCl.sbsp.3                                                              3400, 1770, 1705, 1650, 1520,                                                 1432, 1345, 1107                                                NMRδ (CDCl.sub.3):                                                                    1.35(3H, d, J=6.0Hz), 1.36(3H,                                                d,                                                                            J=7.0Hz), 5.20(2H, s),                                                        5.36(2H,                                                                      ABq, J=13.5Hz), 7.46(2H, d,                                                   J=8.8Hz), 7.64(2H, d,                                                         J=8.8Hz),                                                                     8.21(2H, d, J=8.8Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       293                                    HE  H  H                                                                                 ##STR307##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1760, 1615, 1390, 1245, 1100        66 HE  PNZ                                                                              PNB                                                                               ##STR308##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1770, 1705, 1656, 1525, 1345,                                                 1112                                                            NMRδ (CDCl.sub.3):                                                                    1.35(3h, d, J=6.15Hz), 1.36(3H,                                               d,                                                                            J=7.0Hz), 5.22(2H, s),                                                        5.36(2H,                                                                      ABq, J=13.9Hz), 7.50(2H, d,                                                   J=8.0Hz), 7.64(2H, d,                                                         J=8.0Hz),                                                                     8.20(4H, d, J=8.0Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       292                                    HE  H  H                                                                                 ##STR309##    IRν.sub.max.sup. KBr (cm.sup.-1):                                                        1760, 1630(sh), 1605, 1448,                                                   1380, 1245, 1110                    67 HE  PNZ                                                                              PNB                                                                               ##STR310##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1772, 1710, 1650, 1520, 1435,                                                 1400, 1340                                                      NMRδ (CDCl.sub.3):                                                                    1.34(3H, d, J=6.0Hz), 1.35(3H,                                                d,                                                                            J=7.5Hz), 2.25(3H, s), 2.31(4H,                                               s),                                                                           5.22(2H, s), 5.36(2H, ABq,                                                    J=14.1Hz), 7.49(2H, d,                                                        J=8.6Hz),                                                                     7.63(2H, d, J=8.6Hz), 8.20(4H,                                                d,                                                                            J=8.6Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       291                                    HE  H  H                                                                                 ##STR311##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1620, 1442, 1380, 1250        68 HE  PNZ                                                                              PNB                                                                              OCH.sub.3      IRν.sub.max.sup.CHCl.sbsp.3                                                              1775(sh), 1750(sh), 1710,                                                     1605,                                                                         1522, 1345, 1107                                                NMRδ (CDCl.sub.3):                                                                    1.35(3H, d, J=6.4Hz), 1.36(3H,                                                d,                                                                            J=6.8Hz), 3.66 and 3.73(3H,                                                   each                                                                          S), 5.24(2H, s), 5.36(2H, ABq,                                                N                                                                             J=13.2Hz), 7.45(2H, d,                                                        J=8.5Hz),                                                                     7.65(2H, d, J=8.5Hz), 8.22(4H,                                                d,                                                                            J=8.5Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       296                                    HE  H  H  OCH.sub.3      IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1735, 1602, 1390                     ##STR312##                                                                   69 HE  PNZ                                                                              PNB                                                                              N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.CHCl.sbsp.3                                                              3400, 1770, 1708, 1652, 1604,                                                 1523,                                                                         1397, 1342                                                      [α].sub.D.sup.25 -33°                                                          (c=0.10, CHCl.sub.3)                                            NMRδ (CDCl.sub.3):                                                                    1.34(3H, d, J=6.15Hz), 1.39(3H,                                               d,                                                                            J=7.0Hz), 2.97(3H, s), 2.91                                                   and                                                                           3.12(3H, s), 5.21(2H, s),                                                     5.35(2H,                                                                      ABq, J=13.2Hz), 8.20(4H, d,                                                   J=8.6Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       286                                    HE  H  H  N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1630(sh), 1610, 1395,                                                   1250                                70 HE  PNZ                                                                              PNB                                                                               ##STR313##    IRν.sub.max.sup.CHCl.sbsp.3                                                              3400, 1775, 1707, 1642, 1608,                                                 1526, 1445, 1345                                                [α].sub.D.sup.25 -33°                                                          (c=0.11, CHCl.sub.3)                                            NMRδ (CDCl.sub.3):                                                                    1.33(3H, d, J=6.15Hz), 1.40(3H,                                               d,                                                                            J=6.8Hz), 5.20(2H, s), 5.35(2H,                                               ABq,                                                                          J=13.8Hz), 7.47(2H, d,                                                        J=8.8Hz),                                                                     7.64(2H, d, J=8.8Hz), 8.20(2H,                                                d,                                                                            J=8.8Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       288                                    HE  H  H                                                                                 ##STR314##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1760, 1635(sh), 1610, 1450,                                                   1380, 1240                           ##STR315##                                                                   71 HE  PNZ                                                                              PNB                                                                              N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.CHCl.sbsp.3                                                              3400, 1770, 1700, 1650, 1605,                                                 1520,                                                                         1400, 1120                                                      NMRδ (CDCl.sub.3):                                                                    1.33(3H, d, J=6.15Hz), 1.39(3H,                                               d,                                                                            J=6.8Hz), 2.98(3H, s), 2.92                                                   and                                                                           3.12(3H, each s), 5.22(2H, s),                                                5.36(2H, ABq, J=13.5Hz),                                                      7.50(2H,                                                                      d, J=8.6Hz), 7.64(2H, d,                                                      J=8.6Hz),                                                                     8.21(4H, d, J=8.6Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       291                                    HE  H  H  N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1630(sh), 1610, 1390,                                                   1250                                72 HE  PNZ                                                                              PNB                                                                               ##STR316##    IRν.sub.max.sup.CHCl.sbsp.3                                                              3420, 1775, 1710, 1660, 1621,                                                 1528 1420, 1405, 1120                                           NMRδ (CDCl.sub.3):                                                                    1.33(3H, d, J=6.15Hz), 1.40(3H,                                               d,                                                                            J=6Hz), 4.20(2H, br, s),                                                      5.23(2H,                                                                      s), 5.84(2H, s), 7.50(2H, d,                                                  J=8.6Hz), 7.65(2H, d,                                                         J=8.6Hz),                                                                     8.15(2H, d, J=8.6Hz), 8.21(2H,                                                d,                                                                            J=8.6Hz)                                                        UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       283                                    HE  H  H                                                                                 ##STR317##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1750, 1640, 1610, 1455, 1400,                                                 1250                                 ##STR318##                                                                   73 HE  PNZ                                                                              PNB                                                                              N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.CHCl.sbsp.3                                                              3430, 1775, 1710, 1655, 1525,                                                 1350,                                                                         1012                                                            NMRδ (CDCl.sub.3):                                                                    1.34(3H, d, J=6.4Hz), 1.38(3H,                                                d,                                                                            J=6.8Hz), 2.92, 2.94, 2.98 and                                                3.08(6H, each S), 5.21(2H, s),                                                5.36(2H, ABq, J=13.9Hz),                                                      7.50(2H,                                                                      d, J=8.6Hz), 7.65(2H, d,                                                      J=8.6Hz),                                                                     8.21(2H, d, J=8.6Hz)                                            UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       297                                    HE  H  H  N(CH.sub.3).sub.2                                                                            IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1755, 1630(sh), 1600, 1380,                                                   1240                                 ##STR319##                                                                                               [α].sub.D.sup.33 +=°                                                           (c=0.22, THF)                       74 HE  PNZ                                                                              PNB                                                                              NH.sub.2       IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1780, 1680, 1608, 1517, 1381,                                                 1350                                                            NMRδ (CDCl.sub.3):                                                                    1.18(3H, d, J=6Hz), 5.22(2H,                                                  s),                                                                           5.79(1H, s)                                                     UVλ.sub.max.sup.H.sbsp.2.sup.O                                                       322, 255                               HE  H  H  NH.sub.2       IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1762, 1655, 1577, 1376                                          NMRδ (D.sub.2 O):                                                                     1.29(3H, d, J=6.5Hz),                                                         1.75-1.89(1H,                                                                 m), 2.62-2.87(1H, m),                                                         3.00-3.09(1H,                                                                 m), 3.38-3.48(1H, m),                                                         3.65-3.92(2H,                                                                 m), 3.90(1H, dd, J=1.4Hz and                                                  J=6Hz),                                                                       4.17-4.30(1H, m), 5.68(1H, d),                                                J=1.4Hz)                                                        [α].sub.D.sup.27 +48°                                                          (c=0.31, CHCl.sub.3)                   HE  PNZ                                                                              PNB                                                                               ##STR320##    IRν.sub.max.sup.CHCl.sbsp.3                                                              1790, 1706, 1653, 1612, 1420,                                                 1356, 1115                                                      NMRδ (CDCl.sub.3):                                                                    1.36(3H, d, J=6Hz), 5.22(2H,                                                  s),                                                                           5.75(1H, d, J=1.5Hz)                   HE  H  H                                                                                 ##STR321##    IRν.sub.max.sup.KBr (cm.sup.-1):                                                         1765, 1636, 1582, 1365                                          NMRδ (D.sub.2 O):                                                                     1.29(3H, d, J=6.4Hz),                                                         1.80-2.08(5H,                                                                 m), 2.88-3.05(1H, m),                                                         3.34-3.61(5H,                                                                 m), 3.64-3.74(1H, m), 3.93(1H,                                                dd,                                                                           J=1.4Hz and J=6Hz), 4.04(1H,                                                  quin,                                                                         J=6.6Hz), 4.24(1H, quin,                                                      J=6.3Hz),                                                                     4.40(1H, t, J=8.2Hz), 5.770(1H,                                               d,                                                                            J=1.4Hz)                             ##STR322##                                                                   76 H   PNZ                                                                              PNB                                                                              NH.sub.2       IRν.sub.max.sup.Nujol (cm.sup.-1):                                                       1780, 1700, 1675, 1600, 1505                                    NMRδ (CDCl.sub.3):                                                                    4.40(1H, t, J=7Hz), 5.25(2H,                                                  s),                                                                           5.37(1H, d, J=13.6Hz), 5.75(1H,                                               dd,                                                                           J=1.5Hz and J=3.5Hz), 7.47(2H,                                                d,                                                                            J=9Hz), 7.57(2H, d, J=9Hz),                                                   8.16(4H, d, J=9Hz)                  __________________________________________________________________________

According to the procedures as described in preceding Examples, thefollowing compounds can also be prepared. In the following Tables, "Ph"means phenyl group.

    ______________________________________                                        Compound                                                                      No.      X         Y                                                          ______________________________________                                         ##STR323##                                                                    1       CH.sub.2  NHC.sub.2 H.sub.5                                           2       CH.sub.2  NHnC.sub.4 H.sub.9                                          3       CH.sub.2  NHiC.sub.4 H.sub.9                                          4       CH.sub.2  N(nC.sub.3 H.sub.7).sub.2                                   5       CH.sub.2  N(iC.sub.3 H.sub.7).sub.2                                   6       CH.sub.2  N(nC.sub.4 H.sub.9).sub.2                                   7       CH.sub.2  N(iC.sub.4 H.sub.9).sub.2                                   8       CH.sub.2                                                                                 ##STR324##                                                 9       CH.sub.2                                                                                 ##STR325##                                                10       CH.sub.2                                                                                 ##STR326##                                                11       CH.sub.2                                                                                 ##STR327##                                                12       CH.sub.2                                                                                 ##STR328##                                                13       CH.sub.2  N(CH.sub.2 Ph).sub.2                                       14       CH.sub.2                                                                                 ##STR329##                                                15       CH.sub.2                                                                                 ##STR330##                                                16       CH.sub.2                                                                                 ##STR331##                                                17       CH.sub.2                                                                                 ##STR332##                                                18       CH.sub.2                                                                                 ##STR333##                                                19       CH.sub.2                                                                                 ##STR334##                                                20       CH.sub.2                                                                                 ##STR335##                                                21       CH.sub.2                                                                                 ##STR336##                                                22       CH.sub.2                                                                                 ##STR337##                                                23       CH.sub.2                                                                                 ##STR338##                                                24       CH.sub.2                                                                                 ##STR339##                                                25       CH.sub.2                                                                                 ##STR340##                                                26       CH.sub.2                                                                                 ##STR341##                                                27       CH.sub.2                                                                                 ##STR342##                                                28       CH.sub.2                                                                                 ##STR343##                                                29       CH.sub.2                                                                                 ##STR344##                                                30       CH.sub.2                                                                                 ##STR345##                                                31       CH.sub.2                                                                                 ##STR346##                                                32       CH.sub.2                                                                                 ##STR347##                                                33       CH.sub.2                                                                                 ##STR348##                                                34       CH.sub.2                                                                                 ##STR349##                                                35       CH.sub.2                                                                                 ##STR350##                                                36       CH.sub.2                                                                                 ##STR351##                                                37       CH.sub.2                                                                                 ##STR352##                                                38       CH.sub.2                                                                                 ##STR353##                                                39       CH.sub.2                                                                                 ##STR354##                                                40       CH.sub.2                                                                                 ##STR355##                                                41       CH.sub.2                                                                                 ##STR356##                                                42       CH.sub.2                                                                                 ##STR357##                                                43       CH.sub.2                                                                                 ##STR358##                                                44                                                                                      ##STR359##                                                                              ##STR360##                                                45                                                                                      ##STR361##                                                                              ##STR362##                                                46                                                                                      ##STR363##                                                                              ##STR364##                                                47                                                                                      ##STR365##                                                                              ##STR366##                                                48                                                                                      ##STR367##                                                                              ##STR368##                                                49       S                                                                                        ##STR369##                                                50       S                                                                                        ##STR370##                                                51       S                                                                                        ##STR371##                                                52       S                                                                                        ##STR372##                                                53       S                                                                                        ##STR373##                                                54       S                                                                                        ##STR374##                                                55       S                                                                                        ##STR375##                                                56       S                                                                                        ##STR376##                                                57       S                                                                                        ##STR377##                                                58       S                                                                                        ##STR378##                                                59       S                                                                                        ##STR379##                                                60       S                                                                                        ##STR380##                                                61       S         OCH.sub.3                                                   ##STR381##                                                                   62                                                                                      ##STR382##                                                                              ##STR383##                                                63                                                                                      ##STR384##                                                                              ##STR385##                                                64       CH.sub.2                                                                                 ##STR386##                                                65       CH.sub.2                                                                                 ##STR387##                                                66       S                                                                                        ##STR388##                                                67       S                                                                                        ##STR389##                                                68       S                                                                                        ##STR390##                                                69       S         N(CH.sub.3).sub.2                                           ##STR391##                                                                   70                                                                                      ##STR392##                                                                              ##STR393##                                                71                                                                                      ##STR394##                                                                              ##STR395##                                                72       CH.sub.2                                                                                 ##STR396##                                                73       CH.sub.2                                                                                 ##STR397##                                                74       S                                                                                        ##STR398##                                                75       S                                                                                        ##STR399##                                                76       S                                                                                        ##STR400##                                                77       S         N(CH.sub.3).sub.2                                           ##STR401##                                                                   78                                                                                      ##STR402##                                                                              ##STR403##                                                79                                                                                      ##STR404##                                                                              ##STR405##                                                80                                                                                      ##STR406##                                                                              ##STR407##                                                81                                                                                      ##STR408##                                                                              ##STR409##                                                82                                                                                      ##STR410##                                                                              ##STR411##                                                83       CH.sub.2                                                                                 ##STR412##                                                84       CH.sub.2                                                                                 ##STR413##                                                85       CH.sub.2                                                                                 ##STR414##                                                86       CH.sub.2                                                                                 ##STR415##                                                87       S                                                                                        ##STR416##                                                88       S                                                                                        ##STR417##                                                89       S                                                                                        ##STR418##                                                90       S         N(CH.sub.3).sub.2                                           ##STR419##                                                                   91                 NH.sub.2                                                   92                                                                                      ##STR420##                                                          93                 NHCH.sub.2 CONH.sub.2                                      94                                                                                                ##STR421##                                                95                                                                                                ##STR422##                                                96                                                                                                ##STR423##                                                97                                                                                                ##STR424##                                                98                                                                                                ##STR425##                                                99                                                                                                ##STR426##                                                100                OCH.sub.3                                                  ______________________________________                                    

What is claimed is:
 1. A β-lactam compound represented by the formula:##STR427## wherein R₁ represents a 1-hydroxyethyl group or a1-hydroxyethyl group in which the hydroxy group is protected with aprotecting group for a hydroxy group; R₂ represents a hydrogen atom or aprotecting group for an amino group; R₃ represents a hydrogen atom or aprotecting group for a carboxyl group; X represents an unsubstitutedmethylene group and Y represents a group of the formula (2): ##STR428##wherein R₅ and R₆, which may be the same or different, each represents ahydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenylgroup having 3 to 4 carbon atoms, an aralkyl group having 1 to 3 carbonatoms in the alkyl moiety thereof, a substituted alkyl group having 1 to4 carbon atoms wherein said substituent is selected from the groupconsisting of hydroxyl, di-(C₁ -C₃)-alkylamino or carbamoyl, or R₅ andR₆ are taken together to represent an alkylene chain or an alkylenechain via an oxygen atom, a sulfur atom or a (C₁ -C₃)alkyl-substitutednitrogen atom to form, together with the adjacent nitrogen atom, a 4- to7-membered cyclic amino group, and a pharmaceutically acceptable saltthereof.
 2. A β-lactam compound represented by the formula: ##STR429##wherein R₁ represents a 1-hydroxyethyl group or a 1-hydroxyethyl groupin which the hydroxy group is protected with a protecting group for ahydroxy group; R₂ represents a hydrogen atom or a protecting group foran amino group; R₃ represents a hydrogen atom or a protecting group fora carboxyl group; X represents a substituted methylene group of theformula (1): ##STR430## wherein R₄ represents an alkyl group having 1 to3 carbon atoms; and Y represents a group of the formula (2): ##STR431##wherein R₅ and R₆, which may be the same or different, each represents ahydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkylgroup having 1 to 3 carbon atoms in the alkyl moiety thereof, asubstituted alkyl group having 1 to 4 carbon atoms wherein saidsubstituent is selected from the group consisting of hydroxyl, di-(C₁-C₃)-alkylamino or carbamoyl, or R₅ and R₆ are taken together torepresent an alkylene chain or an alkylene chain via an oxygen atom, asulfur atom or a (C₁ -C₃)-alkyl-substituted nitrogen atom to form,together with the adjacent nitrogen atom, a 4- to 7-membered cyclicamino group, and a pharmaceutically acceptable salt thereof.
 3. Acompound as claimed in claim 1 or 2, wherein R₁ represents a1-hydroxyethyl group, R₂ and R₃ each represents a hydrogen atom.
 4. Acompound as claimed in claim 1 or 2, wherein R₁ represents a1-hydroxyethyl group, R₂ and R₃ each represents a hydrogen atom, and Yis a group represented by the formula (2-c): ##STR432## wherein R_(5-c)and R_(6-c) have either one of the following meanings: (1) R_(5-c)represents an alkyl group having 1 to 4 carbon atoms which may besubstituted with a carbamoyl group, or a hydroxyl group, and R_(6-c)represents a hydrogen atom or has the same meaning as defined forR_(5-c) ;(2) R_(5-c) and R_(6-c) jointly represent an alkylene chain toform, together with the adjacent nitrogen atom, an unsubstituted 4- to6-membered saturated cyclic amino group; and (3) R_(5-c) and R_(6-c)jointly represent an alkylene chain via an oxygen atom or a (C₁-C₃)alkyl-substituted nitrogen atom to form, together with the adjacentnitrogen atom, a 6-membered cyclic amino group.
 5. A β-lactam compoundof the formula: ##STR433## wherein Y is chosen from the group consistingof ##STR434## and the pharmaceutically acceptable salts thereof.
 6. Aβ-lactam compound of the formula: ##STR435## wherein Y is selected fromthe group consisting of ##STR436##
 7. A compound as claimed in claim 3,wherein Y is represented by the formula: ##STR437##
 8. A compound asclaimed in claim 2, 3, 4, or 7, wherein X represents ##STR438## 10.(5R)-3-[2-((1-Pyrrolidino)carbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 11.(5R)-3-[2-((1-Azetidino)carbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 12.(5R)-3-[2-((2-Hydroxyethyl)methylaminocarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-3-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 13.(5R)-3-[2-(1-Morpholinocarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 14.(5R)-3-[2-(1-N-Methylpiperazinocarbonyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 15.(5S)-3-[2-Carbamoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 16.(5S)-3-[2-(Dimethylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 17.(5S)-3-[2-((1-pyrrolidino)carbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 18.(5S)-3-[2-((1-Azatidino)carbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 19.(5S)-3-[2-((2-Hydroxyethyl)methylaminocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 20.(5S)-3-[2-(1-Morpholinocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 21.(5S)-3-[2-(1-N-Methylpiperazinocarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof. 22.(5S)-3-[2-Carbamoylpyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7-one-carboxylicacid, or a non-toxic pharmaceutically acceptable salt thereof.
 23. Apharmaceutical composition for antimicrobial use which comprises as anactive ingredient a pharmaceutically effective amount of at least one ofthe compounds as claimed in claim 1 or claim 2 and at least onepharmaceutically acceptable inert carrier or diluent.
 24. A method oftreating a bacterial infection comprising administering an effectiveamount of a compound according to claim 1 or claim 2 as an antimicrobialagent.
 25. A (5R)-compound of the compound as claimed in claim 1, 3, or7, which is represented by the formula: ##STR439##
 26. A (5S)-compoundof the compound as claimed in claim 2, 3, or 7, which is represented bythe formula: ##STR440##
 27. A (5R,6S,8R)-compound of the compound asclaimed in claim
 22. 28. A (5S,6S,8R)-compound of the compound asclaimed in claim
 27. 29. A (5R,6S,8R)-compound of the compound asclaimed in any one of claims 10, 11, 12, 13, 14 or
 15. 30. A(5S,6S,8R)-compound of the compound as claimed in any one of claims 13,17, 18, 19, 20, 21, or 22
 31. A (5R,6S,8R,2'S,4'S)-compound of thecompound as claimed in claim
 22. 32. A (5S,6S,8R,2'S,4'S)-compound ofthe compound as claimed in claim
 31. 33. A (5R,6S,8R,2'S,4'S)-compoundof the compound as claimed in any one of claims 10, 11, 12, 13, 14 or15.
 34. A (5S,6S,8R,2'S,4'S)-compound of the compound as claimed in anyone of claims 13, 17, 18, 19, 20, 21, or
 22. 35. A β-lactam compound ofthe formula: ##STR441## and the pharmaceutically acceptable saltsthereof.
 36. A β-lactam compound of the formula: ##STR442## and thepharmaceutically acceptable salts thereof.
 37. A β-lactam compound ofthe formula: ##STR443## wherein Y is chosen from the group consisting of##STR444## and the pharmaceutically acceptable salt thereof.
 38. A(5S)-compound of the compound as claimed in claim 8, which isrepresented by the formula: ##STR445##
 39. A(4R,5S,6S,8R,2'S,4'S)-compound of the compound as claimed in any one ofclaims 2, 8, 18, 19, 20, 21 or 22.